Immunization in Alzheimer’s disease: Naïve hope or realistic clinical potential?

There has been considerable recent interest in vaccination of patients by immunotherapy as a potentially clinically useful methodology for combating histopathological changes in Alzheimer\u27s disease (AD). The focus of the majority of this research has been on (1) active immunotherapy using the pre-aggregated synthetic β-amyloid (Aβ) 42 preparation AN1792 vaccine (QS-21), or (2) passive immunization using injections of already prepared polyclonal anti-Aβ antibodies (intravenous immunoglobulin). These two clinical approaches to the treatment of patients with AD represent the focus of this review. We conclude here that, with certain caveats, immunization offers further potential as a technique for the treatment (and possible prevention) of AD. New studies are seeking to develop and apply safer vaccines that do not result in toxicity and neuroinflammation. Nevertheless, caution is warranted, and future clinical investigations are required to tackle key outstanding issues. These include the need to demonstrate efficacy in humans as well as animal models (especially with respect to the potentially toxic side effects of immunotherapy), and fine-tuning in safely guiding the immune response. The issue of defining necessary and sufficient criteria for determining clinical efficacy remains an additional important issue for future immunization trials. The vaccination methodology appears to offer substantial current promise for clearing both soluble and aggregated amyloid in AD. However, it remains to be determined whether this approach will help to repair already damaged neural systems in the disease, and the extent to which vaccination-driven amyloid clearance will impact beneficially on patients\u27 neurocognitive capacity and their functional status. The outcomes of future studies will be important both clinically and scientifically: an important further test of the validity of the amyloid hypothesis of AD is to evaluate the impact of an effective anti-amyloid strategy on the functional status of patients with this disease

Japhetic grammatology

Nikolai Marr has attracted scholarly attention, but largely in a cautionary manner. His work is read as an ideological incursion into the science of language. More charitable assessments contextualize him within oriental studies in the Russian Empire and, in turn, early Soviet nationality policy. Yet ever since his fall from official favour in 1950, scholars have been reluctant to assess his scholarly contributions on their own merit. This essay is an attempt to reconsider Marr by historicizing the mainstream school of thought against which he is compared and found wanting. The pivotal figure for linguistics as we know it today was Ferdinand de Saussure, whose rigorous separation of the systematic synchronic moment of language from its protean historical existence solved a problem which had confounded his contemporaries. It made it possible to treat language as systematic from moment to moment, despite being subject to unforeseeable factors when viewed through time. In drawing this distinction Saussure fatefully privileged speech over writing as the truest instantiation of language. This allowed existing scientific-racist assumptions about the determining influence of anatomy on speech to remain unchallenged. Marr’s early career paralleled that of Saussure’s, yet when it came to the philosophy of language he started from very different premises. Marr identified the origin of language with gesture and tool use. His understanding of evolution departed radically from the organicism common to his contemporaries. Marr’s empirical statements about language are fanciful and cannot easily be recuperated. However, his work represents a tantalizing path not taken in the history of linguistics. As such it is worth reading Marr in the light of Derrida’s reading of Saussure. By bringing Marr into dialogue with better-known thinkers, and historicizing Derrida’s inaugural act of deconstruction, we can sketch the contours of a counter-tradition in linguistics

Amyloid-modifying therapies for Alzheimer’s disease: therapeutic progress and its implications

Alzheimer’s disease (AD) is the most prevalent form of dementia, affecting an estimated 4.8 million people in North America. For the past decade, the amyloid cascade hypothesis has dominated the field of AD research. This theory posits that the deposition of amyloid-beta protein (Aβ) in the brain is the key pathologic event in AD, which induces a series of neuropathological changes that manifest as cognitive decline and eventual dementia. Based on this theory, interventions that reduce Aβ burden in the brain would be expected to alleviate both the neuropathological changes and dementia, which characterize AD. Several diverse pharmacological strategies have been developed to accomplish this. These include inhibiting the formation of Aβ, preventing the aggregation of Aβ into insoluble aggregates, preventing the entry of Aβ into the brain from the periphery and enhancing the clearance of Aβ from the central nervous system. To date, no amyloid-modifying therapy has yet been successful in phase 3 clinical trials; however, several trials are currently underway. This article provides a review of the status of amyloid-modifying therapies and the implications for the amyloid cascade hypothesis