Evolutionary rather than revolutionary progress in dementia

Abstract

Listen

Translate article

Refinements in diagnostic imaging such as structural and functional MRI, SPECT/PET, diffusion tensor imaging, and the identification of biomarkers for Alzheimer’s disease (AD) will allow better discrimination between different types of dementia, detection of preclinical disease states, and monitoring of therapeutic responses. These sophisticated developments may, however, have little relevance in developing countries confronted daily by malnutrition and poverty. By 2025, three-quarters of the world’s population above the age of 60, primarily women, will live in developing countries, where too little dementia research has been done. One of the leading reports this year was, therefore, from the 10/66 Dementia Research Group, 1 which described the development and testing of diagnostic instruments and procedures in a large number of centres in China, India, southeast Asia, Latin America, the Caribbean, and Africa. A simple, predictive, one-stage algorithm that was both sensitive and specific across cultures, and readily useable by trained lay interviewers, was derived. We look forward to future reports by the 10/66 consortium on the epidemiology of dementia in understudied areas of the world. By 2020, cardiovascular diseases, cancers, and diabetes will replace communicable diseases as leading causes of death. Therefore, several vascular risk factors—such as diabetes, hyperglycaemia, insulin resistance, obesity, and hypertension, all of which continued to be implicated in AD during 2003—may play an important part, together with low education, in the development of dementia worldwide. There are also cross-cultural differences in the role of susceptibility genes, such as APOE, for dementia. The role of genes is pivotal to understanding the risk and etiology of dementia, but is not likely to tell the whole story without exploration of gene–environment interactions. During 2003, innate factors that may influence familial and sporadic dementia risk focused on the role of chromosome 10, and stressed the importance of a complex interplay between vascular and genetic factors in AD. For example, selective deletion of the gene coding for insulin degrading enzyme (IDE) was associated with hyperinsulinaemia and amyloid deposition in the brains of mice. 2 Add to this the finding from the Rotterdam study that insulin resistance and type-2 diabetes were related to brain atrophy in individuals without dementia, and insulin is further implicated in AD susceptibility. Of clinical importance this year was a report that silent infarcts on MRI, previously thought to be of little relevance, were related to increased incidence of dementia, including AD. 3 Neuropathology studies, such as the MRC-FAS and the Nun Study, show that only 50% of individuals who fulfilled neuropathological criteria for AD were demented during life. Cerebrovascular disease may be one factor that modifies clinical expression of AD. In patients with silent infarcts, modifiable risk factors—such as hypertension, high cholesterol, or atrial fibrillation—should be treated. Progress related to the treatment of AD included memantine, an N-methyl-D-aspartate (NMDA) receptor antagonist, which may enhance memory by blocking glutamate neurotransmission. Memantine reduced clinical deterioration in patients with moderate-to-severe AD in a placebocontrolled trial, 4 and was approved in the USA this year and the European Union last year. Thus, there is now one more way to treat dementia symptoms, and memantime may also have beneficial effects on the underlying disease pathology due to its influence on glutamate metabolism, decreasing neuronal cell death caused by calcium influx. Furthermore, during 2003, acetylcholinesterase inhibitors were shown to relieve symptoms in dementias related to cerebrovascular disease. Whether a combination of acetylcholinesterase inhibitors and memantine has an additive effect remains to be seen. Emphasis is now shifting from symptom treatment to potentially disease-modifying strategies, such as immunisation and amyloid aggregation inhibitors. AD prevention is being addressed in a number of clinical trials of potential protective agents, such as cholesterollowering statins, Gingko biloba, B vitamins, and non-steroidal anti-inflammatory drugs. Negative results from a placebocontrolled clinical trial of postmenopausal hormone replacement therapy (HRT) were reported in 2003. The Women’s Health Initiative Memory Study (WHIMS) 5 even suggested an unexpected, albeit small, increased risk of dementia for one type of HRT (Premarin; estrogen plus progestin). However, the story on postmenopausal HRT and cognition is not over. Most animal studies showing a protective effect of estrogen have used 17--estradiol. In addition, in WHIMS, women were potentially past the age when estrogen is protective, and the 4-year follow-up was short. The Cache County study reported that recent use of HRT increased AD risk, but longer follow-up suggested the opposite. Similar temporal associations have been reported for overweight, blood pressure, and cholesterol. Thus, the timing of potential risk or benefit factors related to AD always needs to be considered. The estrogen alone arm of the WHIMS trial continues.