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Ebook: Thinking about Cognition: Concepts, Targets and Therapeutics
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100 Years after the discovery of Alzheimer’s disease, neurological diseases and psychiatric disorders represent the largest and fastest growing unmet medical market with 2 billion affected people worldwide. Life expectancy of humans continues to increase, and the world population is aging. Advanced age may lead to deterioration of cognitive functions of the brain. There seems to be consensus that on the background of aging, several factors may render humans prone to dementia. Psychiatric and neurological disorders such as schizophrenia, bipolar disorder or Parkinson’s disease may contribute to development of dementia. More people today are looking for help regarding their learning and memory capabilities. Although increasing knowledge on neuronal networks is transforming our view of the human brain and its function and we understand psychiatric and neurological diseases better today than ever before, novel therapies are needed to respond to the growing demand of patients for assistance with memory loss and learning impairment. In fact, it is expected that novel therapies aiming at the processing of amyloid, or at activation of glutamatergic or nicotinergic systems will demonstrate adequate efficacy in improving learning and memory disturbances. This publication stands as a comprehensive overview of the cellular and molecular mechanisms underlying the development of cognitive impairment. It integrates discoveries concerning dementia, such as mild cognitive impairment and Alzheimer’s disease associated dementia, vascular dementia, retardation syndromes, and psychiatric and neurological disorders related cognitive impairments. This book will be useful to physicians, biologists, and those pursuing an interest or concerned with memory impairment. 100 Years after the discovery of Alzheimer’s disease, neurological diseases and psychiatric disorders represent the largest and fastest growing unmet medical market with 2 billion affected people worldwide. Life expectancy of humans continues to increase, and the world population is aging. Advanced age may lead to deterioration of cognitive functions of the brain. There seems to be consensus that on the background of aging, several factors may render humans prone to dementia. Psychiatric and neurological disorders such as schizophrenia, bipolar disorder or Parkinson’s disease may contribute to development of dementia. More people today are looking for help regarding their learning and memory capabilities. Although increasing knowledge on neuronal networks is transforming our view of the human brain and its function and we understand psychiatric and neurological diseases better today than ever before, novel therapies are needed to respond to the growing demand of patients for assistance with memory loss and learning impairment. In fact, it is expected that novel therapies aiming at the processing of amyloid, or at activation of glutamatergic or nicotinergic systems will demonstrate adequate efficacy in improving learning and memory disturbances. This publication stands as a comprehensive overview of the cellular and molecular mechanisms underlying the development of cognitive impairment. It integrates discoveries concerning dementia, such as mild cognitive impairment and Alzheimer’s disease associated dementia, vascular dementia, retardation syndromes, and psychiatric and neurological disorders related cognitive impairments. This book will be useful to physicians, biologists, and those pursuing an interest or concerned with memory impairment.
“The Solvay Pharmaceuticals Conferences: where industry meets academia in a search for novel therapies”
A Disease of the Future: What Alois Alzheimer did not know?
When Alois Alzheimer admitted his 51 year old patient named Auguste Deker to the Städtische Anstallt für Irre und Epileptische in Frankfurt/Main in 1906, she did not know her last name. One month after her admission she lost memory of her first name, continued to deteriorate rapidly and died shortly thereafter. Auguste Deker was not an unusual case for Alois Alzheimer when categorized according to the medical standards of his time. “Greisenblödheit”, “schleichender Irrsinn” or “Gehirnerweichung” were the common diagnoses describing such cases. However, Alois Alzheimer recognized that this case was unusual. Therefore, he spoke to Auguste Deker almost every day, watching the progress of her disease. After her death, he opened her skull and sectioned her brain. He saw masses of proteins (called today “plaques”) in the cortex of her brain. Alois Alzeimer did not know that he was discovering the cause of one of the most devastating neurological diseases of human kind, called today after his name: Alzheimer's disease. He reported his observations in the lecture entitled “Über eine eigenartige Erkrankung der Hirnrinde” to the 37th Annual Meeting of German Psychiatrists (37. Versammlung Südwestdeutscher Irrenärzte) on November 2, 1906 at the University of Tübingen, suggesting that there might be an organic cause for memory loss [1], a breakthrough concept which has guided medicine for the last century in the search for therapy for Alzheimer's disease.
Today, neurological diseases and psychiatric disorders represent the largest and fastest growing unmet medical market with 2 billion affected people worldwide. Life expectancy of humans continues to increase, and the world population is aging. Advanced age may lead to deterioration of cognitive functions of the brain. The World Health Organization estimates that in the USA alone in 2030 more than 58 million adults will be aged 65 and more, and the fact that many of them will suffer from memory impairment is worrisome. The global incidence of Alzheimer's disease ranges between 15–18 million and is projected to double in the year 2025 to 34 million people. Thus, aging-associated memory impairment represents one of the major health problems of modern society. The reasons for a high propensity of humans to cognitive deterioration are not well understood. There seems to be consensus that on the background of aging, several factors may render humans prone to dementia. Psychiatric and neurological disorders such as schizophrenia, bipolar disorder or Parkinson's disease may contribute to development of dementia.
More people are looking today for help regarding their learning and memory capabilities. Although increasing knowledge on neuronal networks is transforming our view of the human brain and its function and we understand psychiatric and neurological diseases better today than ever before, novel therapies are needed to respond to the growing demand of patients for assistance with memory loss and learning impairment.
Building on decades of brain research and success in revealing how the human brain functions, we arrive at therapies improving the situation of humans suffering from dementia. In addition, progress in knowledge on learning and memory has contributed to the invention of pharmacological measures aiming to help humans improve impaired cognition. Acetylcholine esterase inhibitors such as donepezil, galantamine and rivastigmine and glutamate antagonists such as memantine were introduced to improve memory in dementia patients and have already changed therapy of cognitive impairment [2], reducing behavioral, functional and cognitive deterioration of the patients. However, the introduction of these drugs has not yet closed the gap for therapies improving cognition.
In fact, it is expected that novel therapies aiming at the processing of amyloid, or at activation of glutamatergic or nicotinergic systems, will demonstrate adequate efficacy in improving learning and memory disturbances enabling effective and safe long-term treatment and by doing so will minimize the impact of dementia on modern society.
The fifth Solvay Pharmaceuticals Conference entitled “Thinking about Cognition: Concepts, Targets and Therapeutics” was organized in Miami (Florida) from February 26 to 27, 2004. This conference attracted leaders in cognition research and provided state-of-the-art contributions on mechanisms and on therapy of cognitive disorders today.
The current volume stands as a comprehensive overview of the cellular and molecular mechanisms underlying the development of cognitive impairment. It integrates discoveries concerning dementia, such as mild cognitive impairment and Alzheimer's disease associated dementia, vascular dementia, retardation syndromes, and psychiatric and neurological disorders related cognitive impairments. This book will be useful to physicians, biologists, and those pursuing an interest or concerned with memory impairment.
W. Cautreels, C. Steinborn, L. Turski
References
[1] A. Alzheimer. Über eine eigenartige Erkrankung der Hirnrinde. University of Tübingen (1907). A. Alzheimer, R.A. Stelzmann, H.N. Schnitzlein and F.R. Murtagh. An English translation of Alzheimer's 1907 paper, “Uber eine eigenartige Erkankung der Hirnrinde”. Clin. Anat. 8 (1995) 429–431.
[2] M.S. Wolfe. Therapeutic strategies for Alzheimer's disease. Nat. Rev. Drug Discov. 1 (2002) 859–866.
The meaning of cognition in society is a complex and evolving topic which we explore first by examining the roots of the words themselves: cognition as knowledge together. We then examine three domains of academic and clinical activity surrounding the concept of cognition: cognitive impairment, enhancement and science. Using specific and personal examples we examine the continuum of cognitive ageing from Mild Cognitive Impairment to Alzheimer's disease and from normality to supernormal. Improving our knowledge about cognition and assisting those challenged to preserve their cognitive vitality will require new approaches to our scientific efforts, bridging science with the arts and technology and knowledge with values. We illustrate this approach by focusing on organizational development activities in Cleveland designed to contribute to making Case Western Reserve University at the heart of the world's most powerful learning organization.
Clinical trials are now underway in an attempt to develop effective treatments for older adults who have experienced gradual memory loss since early adult life but who are clearly not demented. The diagnostic entity Age-Associated Memory Impairment (AAMI) is discussed, as are issues related to clinical trials for the indication.
Cognition is impaired in patients with Alzheimer's disease and related disorder (ADRD). The deficits in AD involve verbal and visual memory, and language disturbances in early stages. Cognitive deficits in vascular dementia are variable and overlap with both AD and other dementias. Cognitive deficits in dementia with Lewy bodies involve significant attentional impairment and visual-spatial dysfunction. Cognitive deficits in frontotemporal dementias involve executive function. An assessment of cognition is recommended during initial assessment of patients with dementia. ChEIs and memantine are currently the best drugs available for symptomatic treatment of cognitive decline in patients with ADRD.
Cognitive impairments are present in most patients with schizophrenia and are a major determinant of functional impairments. Before trying to treat cognition with a goal of improving functional disability, it is important to determine that these deficits are not an artifact of other aspects of the illness. This chapter reviews the evidence regarding the primary nature of these cognitive impairments. After reviewing the literature, the conclusion that cognitive deficits are central feature of the illness appears supported. There is remarkably little evidence to suggest that these impairments are caused by other aspects of the illness, despite the flagrant nature of many of these symptoms.
Abnormal cognition is integral to our understanding of depression and mania according to diagnostic criteria, symptoms, and psychological models. In the present chapter, we highlight the use of neuro-imaging techniques and neurocognitive tests to investigate core cognitive abnormalities in patients, with a focus on affective processing bias, response to negative feedback, and decision-making. We also highlight the utility of cognitive tests as objective markers of brain function that may help elucidate aetiological contributions, monitor treatment response, and develop more effective treatment algorithms for mood disorders.
Strategies are described that enable extrapolation of experimental findings from animal studies to the clinic relevant to the treatment of cognitive dysfunction. A paradigm is discussed in rats that enables the specification of elementary processes of executive control, mediated in part by the frontal cortex, and relevant to schizophrenia and other forms of cognitive dysfunction. The rationale for the CANTAB battery is discussed and its utility shown, not only for examining the neuromodulation of fronto-executive processes, but also for investigating the treatment of cognitive dysfunction in neurodegenerative disorders such as Parkinson's and Alzheimer's diseases. The utility of the CANTAB test of paired associates, visuo-spatial learning, for the early detection of Alzheimer's disease and its possible early treatment, is also described.
For the evaluation of pharmacological effects on cognition several animal models are used that measure different aspects of cognition. These models are shortly discussed and positioned in a schematic overview of cognition that consists of a central executive function that directs the information processing between the sensory input, a long-term or reference memory store, two working memory “slave” systems (e.g. the phonological loop and the visuo-spatial sketch path) and the motor output. Subsequently, the effects of CB1 ligands on these cognitive tasks are reviewed. The results seen in the pre-clinical models are in accordance with the memory impairing effects of cannabis in humans. CB1 agonists impair mnemonic performance in the delayed matching to position procedure, in the radial arm maze and in the Morris water maze task. All these effects could be blocked by the CB1 receptor antagonist rimonabant. Furthermore CB1 knock-out mice have been shown to possess enhanced memory in an object recognition task, are impaired in a reversal task in the water maze and show impaired extinction in a tone-shock fear conditioning paradigm. Treatment with the CB1 antagonist rimonabant mimicked the phenotype of the CB1 knock-out mice and in rats rimonabant enhanced social recognition and improved mnemonic performance in the eight arm radial maze. Taken together these data suggest that agonistic activity on the CB1 system mediates extinction and the results from rimonabant indicate that a CB1 antagonist diminishes extinction and therefore enhance long-term memory storage.
In recent years, alterations in the transmission through glutamatergic circuits and changes in glutamate signaling have been proposed to play a key role in the neurochemical disruptions underlying schizophrenia. In particular, the similarities between the symptoms of schizophrenia and the psychotomimetic effects of non-competitive N-methyl-D-aspartate (NMDA) receptor antagonists such as phencyclidine have spurred interest in the possibility that an NMDA receptor hypofunctional state might underlie schizophrenia. A number of recent studies raise the possibility that agents that selectively increase NMDA receptor function while maintaining activity dependence of activation of the NMDA receptor may be useful in treatment of schizophrenia and other disorders that involve cognitive dysfunction. Inhibitors of the glycine transporter GlyT1 may provide a excellent approach for increasing NMDA receptor activation by increasing availability of glycine, which is a necessary co-agonist of this receptor. Also, two G-protein-coupled receptors, M1 muscarinic receptors and mGluR5 metabotropic glutamate receptors that modulate the NMDA receptor, are potential targets for the development of novel compounds that could ameliorate the symptoms of schizophrenia.
Molecular and cellular cognition is a new field whose goal is to derive molecular and cellular explanations of cognitive phenomena, such as learning and memory. This chapter is focused on experiments in this young field that tested the role of synaptic plasticity in hippocampal-dependent learning and memory. Besides experiments documenting changes in synaptic function during learning, most of the evidence supporting a role for synaptic plasticity in memory comes from experiments that either enhance or lesion synaptic processes. Since 1992, mouse knock-outs and transgenics have provided compelling evidence that the molecular mechanisms responsible for the induction and stability of synaptic changes have a critical role in the acquisition and storage of information. There is compelling evidence that besides their role in learning and memory, these mechanisms play a critical role in a number of psychiatric disorders such as schizophrenia, age-related cognitive decline, depression, and drug abuse.
Cognitive deficits are a core feature of schizophrenia. The association between cognitive deficits and poor functional outcome suggest that treatment of cognitive deficits may lead to important functional improvements. However, there are many key components to the methodology of cognitive enhancement clinical trials that must be addressed. This chapter discusses various design features of cognitive enhancement clinical trials for patients with schizophrenia, including inclusion criteria, baseline medication status, baseline level of cognitive impairment, sample size consideration, trial duration, test batteries, and the use of co-primary non-performance measures of cognition with ecological validity.
Dysfunction of frontal circuits may underly impaired cognition in schizophrenia. Impaired cognitive control in schizophrenia may be related to altered function of anterior cingulate cortex and DLPFC. Neuro-imaging studies confirm that deficits in DLPFC are marked at the first episode, while ACC deficits are evident in chronic patients. Cognitive disability in schizophrenia evidenced by fMRI and high density ERP may help to elucidate mechanistic account of schizophrenia and to accelerate drug discovery.
Cognitive impairment is a serious condition which requires specific medication. Cognitive enhancers may target several categorical indications. Cognitive enhancement need to be specific to the condition inducing cognitive impairment. There are no formal guidelines for drug development regarding cognitive impairment. A clear regulatory road map is therefore required to guide clinical trials aiming at development of new drugs improving cognition.
