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Neurological Review |

Translational Research in Neurology:  Dementia

Lawrence S. Honig, MD, PhD
Arch Neurol. 2012;69(8):969-977. doi:10.1001/archneurol.2011.2883.
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Dementia disorders are characterized by clinicopathological criteria. Molecular understandings of these disorders, based on immunohistochemical studies, biochemical investigations, genetic approaches, and animal models, have resulted in advances in diagnosis. Likewise, translational research has allowed us to apply our increasing basic scientific knowledge of neurodegeneration to the rational development of new investigational therapies based on our current understanding of disease pathogenesis. This review discusses the application of translational research to both diagnosis and treatment of dementia disorders. The development of biomarkers has yielded imaging and biochemical methods that assist the physician more than ever in the diagnosis of neurodegenerative dementias, especially Alzheimer disease. New diagnostic criteria for disease are based on these molecular-based techniques. And these biomarkers are of potential use in monitoring disease activity during therapeutic trials. Translational investigations likewise have led toward new avenues in targeted dementia research. This is particularly so in the development and testing of disease-modifying treatments that might slow or deter progressive deterioration. Recent clinical trials have not been based on empirical trials of established drugs but, rather, on trials of drugs shown, through experiments in biochemical, cell culture, and animal models, to interfere with known elements of the pathogenetic cascade of Alzheimer disease.

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Grahic Jump Location

Figure. Hypothetical working model of molecular and clinical features of Alzheimer disease (AD). The pathogenetic cascade of AD disease is hypothesized to initially involve either overproduction or impaired clearance of Aβ42 (A). This peptide aggregates into oligomers and then polymeric deposits. Development of diffuse and neuritic plaques ensues, with concomitant depositions of hyperphosphorylated tau as neurofibrillary tangles and neuritic threads. Ultimately, there are synaptic losses and neuronal losses. In parallel to the cascade depicted (A), indicators of the degree to which clinical biomarkers may be present at different stages of the pathogenetic cascade are shown (B); the darker blue color indicates a higher likelihood of the listed biomarker being positive. Thus, early aspects of β-amyloid dysregulation can be detected through decreased Aβ42 in the cerebrospinal fluid (CSF) and through nuclear medicine–based amyloid imaging. Later stages of the cascade show detectable early brain functional changes through positron emission tomography (PET) with fluorodeoxyglucose (FDG), subsequent brain atrophy, cognitive symptoms, and functional change.

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