Alzheimer Disease: New York

Small SA, Duff K. · Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Department of Neurology, Columbia University College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA. · Neuron. · Pubmed #19038212 No free full text.

Abstract: Alzheimer's disease is characterized by abnormal elevation of Abeta peptide and abnormal hyperphosphorylation of the tau protein. The "amyloid hypothesis," which is based on molecular defects observed in autosomal-dominant early-onset Alzheimer's disease (EOAD), suggests a serial model of causality, whereby elevation of Abeta drives other disease features including tau hyperphosphorylation. Here, we review recent evidence from drug trials, genetic studies, and experimental work in animal models that suggests that an alternative model might exist in late-onset AD (LOAD), the complex and more common form of the disease. Specifically, we hypothesize a "dual pathway" model of causality, whereby Abeta and tau can be linked by separate mechanisms driven by a common upstream driver. This model may account for the results of recent drug trials and, if confirmed, may guide future drug development.

Mitsiades N, Correa D, Gross CP, Hurria A, Slovin SF. · Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA. · Semin Oncol. · Pubmed #19027461 No free full text.

Abstract: There is ample preclinical evidence that gonadal steroids (estrogens and androgens) play an important role in central nervous system development and function. The abrupt decline of estrogen levels in women after menopause, and the slower, subtler decline in total and bioavailable testosterone serum levels that occurs in aging men ("andropause," "male menopause," partial androgen deficiency in ageing males [PADAM]), have been implicated in the pathogenesis of cognitive dysfunction prevalent in elderly adults. However, the current clinical evidence supporting hormonal replacement as a neuroprotective therapy is at best inconclusive. Anti-estrogen and anti-androgen hormonal therapies are used in the treatment of breast and prostate carcinomas, respectively. Although generally considered less toxic than conventional cytotoxic chemotherapy, these hormonal manipulations have side effects that are not trivial. This review will summarize the available evidence regarding the impact of these hormonal therapies on cognitive function in older adults. Additional clinical research in this field is needed to confirm the existence and severity of such a possible cognitive impact, which may then need to be considered prior to initiating hormonal therapies in the elderly, as many patients may be in the prodromal phase or early stages of a neurodegenerative disorder, such as Alzheimer's disease, and this information may influence treatment decision-making and subsequent management.

Koppel J, Davies P. · The Albert Einstein College of Medicine and The Litwin-Zucker Research Center for the Study of Alzheimer's Disease and Memory Disorders, The Feinstein Institute for Medical Research, Manhasset, NY 11030, USA. · J Alzheimers Dis. · Pubmed #18997302 No free full text.

Abstract: The endocannabinoid system is rapidly emerging as a potential drug target for a variety of immune-mediated central nervous system diseases. There is a growing body of evidence suggesting that endocannabinoid interventions may have particular relevance to Alzheimer's disease. Here we present a review of endocannabinoid physiology, the evidence that underscores its utility as a potential target for intervention in Alzheimer's disease, and suggest future pathways of research.

Madhusoodanan S, Shah P. · St John's Episcopal Hospital Far Rockaway, NY 11691, USA. · Clin Interv Aging. · Pubmed #18982919 links to  free full text

Abstract: Psychosis of Alzheimer's disease (AD) is characterized by delusions or hallucinations and may be associated with agitation, negative symptoms or depression. There are no psychotropic medications that are approved by the US FDA for the treatment of psychosis of AD. However, atypical antipsychotics have been widely used and recommended by geriatric experts in the management of psychosis of AD in view of the modest efficacy and relative safety until FDA warnings were issued in 2005 and meta-analytic studies showed no significant difference to placebo. The FDA warnings on the cardiac, metabolic, cerebrovascular, and mortality risks have caused serious concerns for the use of atypical antipsychotic agents in elderly patients with dementia. Only a few studies have evaluated prospectively the effects of aripiprazole in psychosis associated with AD. These studies show improvement in the symptoms of psychosis associated with AD with aripiprazole. The safety and tolerability profile of aripiprazole suggests a low potential for negative impact on dementia and overall patient health. Further studies comparing the efficacy and tolerability of aripiprazole vs other atypical antipsychotics in dementia are needed.

Sano M. · Alzheimer's Disease Research Center, Mount Sinai School of Medicine, New York, NY, USA. · CNS Spectr. · Pubmed #18955963 links to  free full text

This publication has no abstract.

Relkin NR. · Weill Cornell Memory Disorders Program, Weill Cornell Medical College, New York, NY, USA. · CNS Spectr. · Pubmed #18955962 links to  free full text

This publication has no abstract.

Iqbal K, Chohan MO, Grundke-Iqbal I. · Department of Neurochemistry, New York State Institute for Basic Research in Developmental Disabilities, 1050 Forest Hill Road, Staten Island, New York, NY 10314, USA. iqbalk@worldnet att.net · J Alzheimers Dis. · Pubmed #18953118 links to  free full text

Abstract: Development of effective neuroprotective drugs for Alzheimer's disease (AD) is a formidable challenge because this disease is multifactorial and heterogeneous. Although AD is characterized histopathologically by the presence of numerous amyloid-beta plaques and neurofibrillary degeneration of abnormally hyperphosphorylated tau in the brain, these two hallmark lesions do not exist in any fixed proportion in this disease. Furthermore, in the brains of some normal aged individuals, there are as many amyloid-beta plaques seen as in typical cases of AD. On the other hand, extensive neurofibrillary degeneration of abnormally hyperphosphorylated tau and dementia but in the absence of amyloid-beta plaques occur in several related neurodegenerative disorders called tauopathies. More than one molecular mechanism has been described for the development of amyloid-beta as well as neurofibrillary degeneration of abnormally hyperphosphorylated tau. Thus, AD apparently results from several different etiopathogenic mechanisms and offers numerous rational therapeutic targets. We have discovered that there are at least five different subgroups of AD, and future studies are likely to identify additional subgroups. The employment of these subgroups of AD in clinical trials can markedly increase the success in developing specific and potent therapeutic drugs.

Sigurdsson EM. · Department of Physiology, New York University School of Medicine, New York, NY 10016, USA. · J Alzheimers Dis. · Pubmed #18953105 No free full text.

Abstract: Immunotherapies that target the amyloid-beta (Abeta) peptide in Alzheimer's disease (AD) have shown promise in animal and human studies. Although the first clinical trial was halted because of adverse reactions, this approach has been refined and additional trials are underway. Another important target in AD is the neurofibrillary tangles, composed primarily of hyperphosphorylated tau proteins, which correlate well with the degree of dementia. As Abeta and tau pathologies are likely synergistic, targeting both should be more effective and may be essential as early diagnosis prior to cognitive decline is currently not available. Also, Abeta immunotherapy only results in a very limited indirect clearance of tau aggregates in dystrophic neurites, showing the importance of developing a separate therapy that directly targets pathological tau. Our findings in two tangle mouse models indicate that immunization with a phospho-tau derivative reduces aggregated tau in the brain and slows progression of the tangle-related behavioral phenotype. These antibodies enter the brain and bind to pathological tau within neurons. We are currently clarifying further the mechanism of action of this promising therapeutic approach and determining its epitope specificity.

Gong CX, Iqbal K. · Department of Neurochemistry, New York State Institute for Basic Research in Developmental Disabilities, Staten Island, New York, USA. · Curr Med Chem. · Pubmed #18855662 links to  free full text

Abstract: Alzheimer disease (AD) is the most common cause of dementia in adults. The current therapy for AD has only moderate efficacy in controlling symptoms, and it does not cure the disease. Recent studies have suggested that abnormal hyperphosphorylation of tau in the brain plays a vital role in the molecular pathogenesis of AD and in neurodegeneration. This article reviews the current advances in understanding of tau protein, regulation of tau phosphorylation, and the role of its abnormal hyperphosphorylation in neurofibrillary degeneration. Furthermore, several therapeutic strategies for treating AD on the basis of the important role of tau hyperphosphorylation in the pathogenesis of the disease are described. These strategies include (1) inhibition of glycogen synthase kinase-3beta (GSK-3beta), cyclin-dependent kinase 5 (cdk5), and other tau kinases; (2) restoration of PP2A activity; and (3) targeting tau O-GlcNAcylation. Development of drugs on the basis of these strategies is likely to lead to disease-modifying therapies for AD.

Sano M, Grossman H, Van Dyk K. · The Alzheimer Disease Research Center of Mount Sinai School of Medicine, New York, New York, USA. · CNS Drugs. · Pubmed #18840031 No free full text.

Abstract: Alzheimer's disease is an ever-increasing health concern among the aging population, and as we research new and existing treatments for this disease we begin to uncover possibilities for its prevention. Observational studies and animal models have provided promising findings and generated excitement, but placebo-controlled clinical trials are required to demonstrate true efficacy for these treatments.In the past two decades, clinical trials have led to the approval of symptomatic treatments for Alzheimer's disease, including cholinesterase inhibitors and, more recently, an NMDA receptor antagonist. Clinical trials have also examined antioxidants, NSAIDs, hormone replacement, nutritional supplements and nonpharmacological interventions for the treatment and prevention of Alzheimer's disease. While the results of many of these trials have been disappointing, new mechanisms targeting the hallmark pathology of Alzheimer's disease are currently under investigation, including immunotherapy and secretase modulation, targeted at reducing the amyloid burden, for which we await the results. We review the evidence from completed trials, support for ongoing studies and propose directions for future research.

Ribe EM, Serrano-Saiz E, Akpan N, Troy CM. · Department of Pathology, Taub Center for the Study of Alzheimer's Disease and the Aging Brain, Columbia University College of Physicians and Surgeons, 630 W. 168th Street, New York, NY 10032, USA. · Biochem J. · Pubmed #18800967 No free full text.

Abstract: Dysregulation of life and death at the cellular level leads to a variety of diseases. In the nervous system, aberrant neuronal death is an outstanding feature of neurodegenerative diseases. Since the discovery of the caspase family of proteases, much effort has been made to determine how caspases function in disease, including neurodegenerative diseases. Although many papers have been published examining caspases in neuronal death and disease, the pathways have not been fully clarified. In the present review, we examine the potential players in the death pathways, the current tools for examining these players and the models for studying neurological disease. Alzheimer's disease, the most common neurodegenerative disorder, and cerebral ischaemia, the most common cause of neurological death, are used to illustrate our current understanding of death signalling in neurodegenerative diseases. A better understanding of the neuronal death pathways would provide targets for the development of therapeutic interventions for these diseases.

Lee JH, Barral S, Reitz C. · Sergievsky Center, 630 W. 168th Street, New York, NY 10032, USA. · Curr Neurol Neurosci Rep. · Pubmed #18713574 links to  free full text

Abstract: Recent studies indicate that two clusters of single nucleotide polymorphisms in the neuronal sortilin-related receptor gene (SORL1) are causally associated with late-onset Alzheimer's disease (AD). At the cellular level, SORL1 is thought to be involved in intracellular trafficking of amyloid precursor protein. When this gene is suppressed, toxic amyloid beta production is increased, and high levels of amyloid betaare associated with a higher AD risk. Extending the cellular findings, gene expression studies show that SORL1 is differentially expressed in AD patients compared with controls. Furthermore, several genetic studies have identified allelic and haplotypic SORL1 variants associated with late-onset AD, and these variants confer small to modest risk of AD. Taken together, the evidence for SORL1 as a causative gene is compelling. However, putative variants have not yet been identified. Further research is necessary to determine its utility as a diagnostic marker of AD or as a target for new therapeutic approaches.

Chauhan V, Ji L, Chauhan A. · New York State Institute for Basic Research in Developmental Disabilities, 1050 Forest Hill Road, Staten Island, New York, 10314, USA. · Biogerontology. · Pubmed #18704746 No free full text.

Abstract: Fibrillar amyloid beta-protein (Abeta) is a major component of amyloid plaques in the brains of individuals with Alzheimer's disease (AD) and of adults with Down syndrome (DS). Gelsolin, a cytoskeletal protein, is present both intracellularly (cytoplasmic form) and extracellularly (secretory form in biological fluids). These two forms of gelsolin differ from each other in length and in cysteinyl thiol groups. Previous studies from our and other groups have identified the anti-amyloidogenic role of gelsolin in AD. Our studies showed that both plasma and cytosolic gelsolin bind to Abeta, and that gelsolin inhibits the fibrillization of Abeta and solubilizes preformed fibrils of Abeta. Other studies have shown that peripheral administration of plasma gelsolin or transgene expression of plasma gelsolin can reduce amyloid load in the transgenic mouse model of AD. Our recent studies showed that gelsolin expression increases in cells in response to oxidative stress. Oxidative damage is considered a major feature in the pathophysiology of AD. Abeta not only can induce oxidative stress, but also its generation is increased as a result of oxidative stress. In this article, we review evidence of gelsolin as an anti-amyloidogenic agent that can reduce amyloid load by acting as an inhibitor of Abeta fibrillization, and as an antioxidant and anti-apoptotic protein.

Alonso AC, Li B, Grundke-Iqbal I, Iqbal K. · Department of Biology and Center for Developmental Neuroscience and Developmental Disabilities, College of Staten Island, The City University of New York, Staten Island, NY 10314, USA. · Curr Alzheimer Res. · Pubmed #18690834 No free full text.

Abstract: The accumulation of hyperphosphorylated tau is a common feature of several dementias. Tau is one of the brain microtubule-associated proteins. Here we discuss tau's function in microtubule assembly and stabilization and with regards to tau's interactions with other proteins, membranes, and DNA. We describe and analyze important posttranslational modifications: hyperphosphorylation, glycosylation, ubiquitination, glycation, polyamination, nitration, and truncation. We discuss how these post-translational modifications can alter tau's biological function and what is known about tau self-assembly, and we propose a mechanism of tau polymerization. We analyze the impact of natural mutations on tau that cause fronto-temporal dementia associated with chromosome 17 (FTDP-1 7). Finally, we consider whether tau accumulation or its conformational change is related to tau-induced neurodegeneration, and we propose a mechanism of neurodegeneration.

Congdon EE, Duff KE. · Taub Institute for Research on Alzheimer's Disease, Department of Pathology, Columbia University, New York, NY, USA. · J Alzheimers Dis. · Pubmed #18688098 No free full text.

Abstract: Abnormal protein deposits are a common feature of many human diseases including Alzheimer's disease. In Alzheimer's disease, the appearance of tangles, composed of the microtubule associated protein tau, correlates with both cell death and symptom severity. However, are tau filaments simply markers of disease progression, or are they directly responsible for cell death? Due to conflicting findings from cell and animal models, it remains controversial whether tau polymers or smaller pre-fibrillar aggregates or tau monomers are the toxic species. Indeed, if monomeric or oligomeric species are mediators of disease, formation of larger tau filaments may prove beneficial to affected cells. This review will examine the findings regarding the toxicity of various tau species.

Bretteville A, Planel E. · Columbia University Medical Center, Taub Institute for Research on Alzheimer's Disease and the Aging Brain, New York, NY 10032, USA. · J Alzheimers Dis. · Pubmed #18688094 No free full text.

Abstract: Alzheimer's disease brains are characterized by extracellular aggregates of the amyloid-beta peptide and intracellular neurofibrillary tangles, composed of aggregated hyperphosphorylated tau protein. The role of aggregated tau in neurodegeneration is still controversial, as evidence point to either a toxic or protective role in the disease. Here, we will first examine tau aggregation and its putative roles in Alzheimer's disease. We will then review the findings concerning different species of tau and their potential toxicity.

Deane R, Sagare A, Zlokovic BV. · Center for Neurodegenerative and Vascular Brain Disorders, University of Rochester, University of Rochester Medical Center, 601 Elmwood Avenue, Rochester, NY 14642, USA. · Curr Pharm Des. · Pubmed #18673201 No free full text.

Abstract: Low-density lipoprotein receptor related protein-1 (LRP) is a member of the low-density lipoprotein (LDL) receptor family which has been linked to Alzheimer's disease (AD) by biochemical and genetic evidence. Levels of neurotoxic amyloid beta-peptide (Abeta) in the brain are elevated in AD contributing to the disease process and neuropathology. Faulty Abeta clearance from the brain appears to mediate focal Abeta accumulations in AD. Central and peripheral production of Abeta from Abeta-precursor protein (APP), transport of peripheral Abeta into the brain across the blood-brain barrier (BBB) via receptor for advanced glycation end products (RAGE), enzymatic Abeta degradation, Abeta oligomerization and aggregation, neuroinflammatory changes and microglia activation, and Abeta elimination from brain across the BBB by cell surface LRP; all may control brain Abeta levels. Recently, we have shown that a soluble form of LRP (sLRP) binds 70 to 90 % of plasma Abeta, preventing its access to the brain. In AD individuals, the levels of LRP at the BBB are reduced, as are levels of Abeta binding to sLRP in plasma. This, in turn, may increase Abeta brain levels through a decreased efflux of brain Abeta at the BBB and/or reduced sequestration of plasma Abeta associated with re-entry of free Abeta into the brain via RAGE. Thus, therapies which increase LRP expression at the BBB and/or enhance the peripheral Abeta "sink" activity of sLRP, hold potential to control brain Abeta accumulations, neuroinflammation and cerebral blood flow reductions in AD.

Wisniewski T, Konietzko U. · Department of Neurology, New York University School of Medicine, New York, NY 10016, USA. · Lancet Neurol. · Pubmed #18667360 No free full text.

Abstract: Alzheimer's disease is the main cause of dementia in elderly people and is becoming an ever greater problem as societies worldwide age. Treatments that stop or at least effectively modify disease course do not yet exist. In Alzheimer's disease, the conversion of the amyloid-beta peptide (Abeta) from a physiological water-soluble monomeric form into neurotoxic oligomeric and fibrillar forms rich in stable beta-sheet conformations is an important event. The most toxic forms of Abeta are thought to be oligomers, and dimers might be the smallest neurotoxic species. Numerous immunological approaches that prevent the conversion of the normal precursor protein into pathological forms or that accelerate clearance are in development. More than ten new approaches to active and passive immunotherapy are under investigation in clinical trials with the aim of producing safe methods for immunological therapy and prevention. A delicate balance between immunological clearance of an endogenous protein with acquired toxic properties and the induction of an autoimmune reaction must be found.

Reisberg B, Prichep L, Mosconi L, John ER, Glodzik-Sobanska L, Boksay I, Monteiro I, Torossian C, Vedvyas A, Ashraf N, Jamil IA, de Leon MJ. · Silberstein Aging and Dementia Research Center, New York University School of Medicine, New York, NY, USA. · Alzheimers Dement. · Pubmed #18632010 No free full text.

Abstract: BACKGROUND: Subjective cognitive impairment (SCI) has been a common, but poorly understood condition, frequently occurring in older persons. METHODS: The past and the emerging literature on SCI and synonymously named conditions is reviewed. RESULTS: Findings include: (1) There is support from at least one longitudinal study for a long-standing concept of SCI as a pre-mild cognitive impairment (MCI) condition lasting approximately 15years. (2) There are complex relationships between SCI and depression and anxiety. (3) Differences in SCI subjects from age-matched non-SCI persons are being published in terms of cognitive tests, hippocampal gray matter density, hippocampal volumes, cerebral metabolism, and urinary cortisol levels. Psychometric and dementia test score differences between SCI and MCI subjects have long been evident. (4) Predictive electrophysiologic features of subsequent decline in SCI subjects are being published. CONCLUSIONS: Studies of therapeutic agents in SCI treatment and resultant Alzheimer's disease prevention appear to be feasible. These trials are also necessary from a public health perspective.

Fillit H. · Executive Director, The Alzheimer's Drug Discovery Foundation, New York, NY, USA. · Alzheimers Dement. · Pubmed #18631996 No free full text.

Abstract: Progress in understanding the pathogenesis of Alzheimer's disease (AD) has advanced rapidly and has achieved parity in knowledge with other chronic degenerative diseases of the elderly. This knowledge has not yet been successfully translated into new and effective disease-modifying drugs. Many new clinical candidates are currently in clinical trials, and it is likely that some will be successful in achieving regulatory approval. Nevertheless, primary prevention of AD remains the ultimate and most important goal of research efforts because the unique clinical features of this dementing disease create a number of challenges for drug development, regulatory approval, and payment. Ultimately, the development of truly effective disease-modifying drugs through accelerated drug discovery is the only real pathway to primary prevention.

Kamer AR, Craig RG, Dasanayake AP, Brys M, Glodzik-Sobanska L, de Leon MJ. · Department of Periodontology and Implant Dentistry, College of Dentistry, New York University, New York, NY, USA. · Alzheimers Dement. · Pubmed #18631974 No free full text.

Abstract: The molecular and cellular mechanisms responsible for the etiology and pathogenesis of Alzheimer's disease (AD) have not been defined; however, inflammation within the brain is thought to play a pivotal role. Studies suggest that peripheral infection/inflammation might affect the inflammatory state of the central nervous system. Chronic periodontitis is a prevalent peripheral infection that is associated with gram-negative anaerobic bacteria and the elevation of serum inflammatory markers including C-reactive protein. Recently, chronic periodontitis has been associated with several systemic diseases including AD. In this article we review the pathogenesis of chronic periodontitis and the role of inflammation in AD. In addition, we propose several potential mechanisms through which chronic periodontitis can possibly contribute to the clinical onset and progression of AD. Because chronic periodontitis is a treatable infection, it might be a readily modifiable risk factor for AD.

Zlokovic BV. · Center for Neurodegenerative and Vascular Brain Disorders, Departments of Neurosurgery, University of Rochester Medical School, Rochester, New York 14642, USA. · Neurotherapeutics. · Pubmed #18625452 links to  free full text

Abstract: Recent findings indicate that neurovascular dysfunction is an integral part of Alzheimer's disease (AD). Changes in the vascular system of the brain may significantly contribute to the onset and progression of dementia and to the development of a chronic neurodegenerative process. In contrast to the neurocentric view, which proposes that changes in chronic neurodegenerative disorders, including AD, can be attributed solely to neuronal disorder and neuronal dysfunction, the neurovascular concept proposes that dysfunction of non-neuronal neighboring cells and disintegration of neurovascular unit function may contribute to the pathogenesis of dementias in the elderly population, and understanding these processes will be crucial for the development of new therapeutic approaches to normalize both vascular and neuronal dysfunction. In this review, I discuss briefly the role of vascular factors and vascular disorder in AD, the link between cerebrovascular disorder and AD, the clearance hypothesis for AD, the role of RAGE (receptor for advanced glycation end products) and LRP (low density lipoprotein receptor related protein 1) in maintaining the levels of amyloid beta-peptide (Abeta) in the brain by controlling its transport across the blood-brain barrier (BBB), and the role of impaired vascular remodeling and cerebral blood flow dysregulation in the disease process. The therapeutic strategies based on new targets in the AD neurovascular pathway, such as RAGE and LRP receptors, and on a few selected genes implicated in AD neurovascular dysfunction (e.g., mesenchyme homeobox gene 2 and myocardin) are also discussed.

Lopachin RM, Gavin T. · Department of Anesthesiology, Albert Einstein College of Medicine, Montefiore Medical Center, 111 East 210th Street, Bronx, New York 10467, USA. · J Agric Food Chem. · Pubmed #18624437 No free full text.

Abstract: Acrylamide (ACR) has demonstrable neurotoxic effects in animals and humans that stem from its chemical behavior as a soft electrophilic alpha,beta-unsaturated carbonyl compound. Evidence is presented that the nerve terminal is a primary site of ACR action and that inhibition of neurotransmission mediates the development of neurological deficits. At the mechanistic level, recent proteomic, neurochemical, and kinetic data are considered, which suggest that ACR inhibits neurotransmission by disrupting presynaptic nitric oxide (NO) signaling. Nerve-terminal damage likely mediates the neurological complications that accompany the occupational exposure of humans to ACR. In addition, the proposed molecular mechanism of synaptotoxicity has substantial implications for the pathogenesis of Alzheimer's disease and other neurodegenerative conditions that involve neuronal oxidative stress and the secondary endogenous generation of acrolein and other conjugated carbonyl chemicals.

Shulman A, Goldstein B, Strashun AM. · Department of Otolaryngology, State University of New York, Downstate Medical Center, Brooklyn, NY 11203, USA. · Int Tinnitus J. · Pubmed #18616086 No free full text.

Abstract: The translation of a neurovascular hypothesis for Alzheimer's disease to subjective idiopathic tinnitus (SIT) is presented as a challenge to the predominantly sensorineural view of SIT and its clinical application for tinnitus treatment. The concept of neurovascular dysfunction and neurodegeneration (ND) in SIT patients has been proposed and reported as an etiology in a particular subset of tinnitus patients with a diagnosis of medical-audiological tinnitus, through a medical-audiological tinnitus patient protocol, to be a predominantly central-type, severe, disabling SIT (n = 54 of 96). A medical-audiological ND tinnitus profile was the basis for selection of 18 SIT patients (n = 18 of 54) for nuclear medicine brain imaging (i.e., single-photon emission computed tomography or positron emission tomography, or both). Objective findings were reported in 16 of this cohort of 18 SIT patients selected for nuclear medicine imaging (88.9%). Classification of central nervous system (CNS) ND and tinnitus differentiated between (1) ND, nonspecific and of unknown etiology; (2) ND manifested by perfusion asymmetries in brain associated with ischemia (n = 11 of 18); and (3) ND CNS disease consistent with nuclear medicine criteria for senile dementia Alzheimer's-type disease (n = 5 of 18). The diagnosis was associated with cerebrovascular disease (n = 16 of 18). The identification of pathological processes of inflammation and ischemia, linked to ND, in a particular cohort of SIT patients may provide a basis for establishing the medical significance and treatment of SIT and influence the clinical course of the tinnitus.

Day M, Balci F, Wan HI, Fox GB, Rutkowski JL, Feuerstein G. · PsychoGenics Inc, Cognitive Neurosciences, 765 Old Saw Mill River Road, Tarrytown, NY 10591, USA. · Curr Opin Investig Drugs. · Pubmed #18600575 No free full text.

Abstract: Cognition is a complex set of processes, including attention, learning and memory, that refers to the capacity to encode, consolidate, store and retrieve recent and remotely stored fact (semantic) and experience-based (episodic) memory. The development of cognitive enhancers is of particular importance to society and the pharmaceutical industry, as cognitive dysfunctions are observed across a wide range of neuropsychiatric and neurodegenerative disorders; however, developing such therapeutics has proven difficult. There is poor congruency between the abundance of positive results observed in animal studies compared with clinical outcome. For example, from 1982 to 2002 there was a 6000% increase in studies on cognitive processing in rodents that had little or no impact on the outcome of phase II and III clinical trials. The effects of therapeutics on models of cognition that demonstrate the potential to improve preclinical-to-clinical congruency, focusing on attention, impulsivity and episodic memory, are summarized in this review. Changes in attention, impulsivity and episodic memory are tractable 'disease biomarkers' that correlate with the disease phenotypes that are potential therapeutic targets. In the context of the development of cognitive enhancing drugs, one of the major goals of translational medicine is to improve the congruency between preclinical models and clinical results. Improved translatability could improve discovery, validation and implementation of biomarkers to inform clinical outcome studies and decision making, and to establish proof-of-concept for efficacy and safety based on targeted mechanisms of action.