Review: Diagnosis and treatment of dementia: 1. Risk assessment and primary prevention of Alzheimer disease

Background

In addition to nonmodifiable genetic risk factors, potentially modifiable factors such as hypertension, hyperlipidemia and environmental exposures have been identified as risk factors for Alzheimer disease. In this article, we provide physicians with practical guidance on risk assessment and primary prevention of Alzheimer disease based on recommendations from the Third Canadian Consensus Conference on the Diagnosis and Treatment of Dementia, held in March 2006.

Methods

We developed evidence-based guidelines using systematic literature searches, with specific criteria for study selection and quality assessment, and a clear and transparent decision-making process. We selected studies published from January 1996 to December 2005 that met the following criteria: dementia (all-cause, Alzheimer disease or vascular dementia) as the outcome; longitudinal cohort study; study population broadly reflective of Canadian demographics; and genetic risk factors and general risk factors (e.g., hypertension, education, occupation and chemical exposure) identified. We graded the strength of evidence using the criteria of the Canadian Task Force on Preventive Health Care.

Results

Of 3424 articles on potentially modifiable risk factors for dementia, 1719 met our inclusion criteria; 60 were deemed to be of good or fair quality. Of 1721 articles on genetic risk factors, 62 that met our inclusion criteria were deemed to be of good or fair quality. On the basis of evidence from these articles, we made recommendations for the risk assessment and primary prevention of Alzheimer disease. For the primary prevention of Alzheimer''s disease, there is good evidence for controlling vascular risk factors, especially hypertension (grade A), and weak or insufficient evidence for manipulation of lifestyle factors and prescribing of medications (grade C). There is good evidence to avoid estrogens and high-dose (> 400 IU/d) of vitamin E for this purpose (grade E). Genetic counselling and testing may be offered to at-risk individuals with an apparent autosomal dominant inheritance (grade B). Screening for the apolipoprotein E genotype in asymptomatic individuals in the general population is not recommended (grade E).

Interpretation

Despite the personal and societal burden of dementia, our understanding of genetic predisposition to dementias and the contribution of other risk factors remains limited. More importantly, there are few data to explain the overall risks and benefits of prevention strategies or their impact of risk modification.

Articles to date in this series

• Chertkow H. Diagnosis and treatment of dementia: Introduction. Introducing a series based on the Third Canadian Consensus Conference on the Diagnosis and Treatment of Dementia. CMAJ 2008;178:316-21.

     

Temperature-jump studies of Desulfovibrio vulgaris flavodoxin: Kinetics of FMN binding and of reduction of semiquinone by methyl viologen

Temperature-jump relaxation spectrometry has been used with the flavodoxin from Desulfovibrio vulgaris to investigate the kinetics of FMN binding to apoprotein and of reduction of half-reduced to fully-reduced protein by methyl viologen. FMN binding was characterized by a single, concentration dependent, exponential relaxation which corresponded to a diminution of flavin fluorescence intensity. This implies the absence of detectable intermediates during coenzyme binding and a positive enthalpy of binding. The latter was confirmed by microcalorimetry and fluorometric titration studies at two temperatures. The reduction of the half-reduced holoprotein also displayed simple exponential kinetics, again implying the absence of intermediates. The results of these studies are compared with earlier work with other flavodoxins.     

Epidemiologic studies on human and feline toxoplasmosis.

Human serological profiles, and feline serological and fecal profiles were used to study the epidemiology of toxoplasmosis in Santa Clara County, California. The prevalence of human toxoplasmosis was determined to be 42.9% in a test population of 147 women. The prevalence of feline toxoplasmosis was indicated to be 34.8% based on serological analysis of 158 felines. Of 107 cats tested, 6.5% were shedding Toxoplasma gondii - like oocysts in their feces. Statistical analyses of questionnaire data indicated that the major infection sources for seropositive humans in this study were: (1) eating rare-medium cooked beef; (2) exposure to cats; and (3) working in an outside garden. Of these three sources, gardening represented the least risk. The data from questionnaires with reference to age, residence, and eating and toilet habits of owned felines were evaluated and found to show no significant statistical correlation with seropositivity. The infection sources for seropositive felines could not be determined. The plausible significance of feline-human interaction, human consumption of infected meat, and gardening habits is stressed.     

Gene expression: chemical synthesis and molecular cloning of a bacteriophage T5 (T5P25) early promoter.

A sixty base pair DNA duplex containing the nucleotide sequence of the bacteriophage T5 early (T5P25) promoter has been constructed using a combination of chemical synthesis and enzymatic methods. Subsequent to cloning into pBR322, the promoter has been demonstrated to be biologically active being capable of directing the efficient expression of genes under its control. This serves as a prototype for an approach to the study of the in vivo structure-function relationships and efficiency of promoters.     

Interaction of ouabain with the Na(+) pump in intact epithelial cells

To determine the specificity and efficacy of [(3)H]ouabain binding as a quantitative measure of the Na(+) pump (Na(+), K(+)-ATPase) and as a marker for the localization of pumps involved in transepithelial Na(+)-transport, we analyzed the interaction of [(3)H]ouabain with its receptor in pig kidney epithelial (LLC-PK(1)) cells. When these epithelial cells are depleted of Na(+) and exposed to 2 muM [(3)H]ouabain in a Na(+)-free medium, binding is reduced by 90 percent. When depleted of K(+) and incubated in a K(+)- free medium, the ouabain binding rate is increase compared with that measured at 5 mM. This increase is only demonstable when Na(+) is present. The increased rate could be attributed to the predominance of the Na(+)-stimulated phosphorylated form of the pump, as K(+) is not readily available to stimulate dephosphorylation. However, some binding in the K(+)-free medium is attributable to pump turnover (and therefore, recycling of K(+)), because analysis of K(+)-washout kinetics demonstrated that addition of 2 muM ouabain to K(+)-depleted cells increased the rate of K(+) loss. These results indicate that in intact epithelial cells, unlike isolated membrane preparations, the most favorable condition for supporting ouabain binding occurs when the Na(+), K(+)-ATPase is operating in the Na(+)-pump mode or is phosphorylated in the presence of Na(+). When LLC-PK(1) cells were exposed to ouabain at 4 degrees C, binding was reduced by 97 percent. Upon rewarming, the rate of binding was greater than that obtained on cells kept at a constant 37 degrees C. However, even at this accelerated rate, the time to reach equilibrium was beyond what is required for cells, swollen by exposure to cold, to recover normal volume. Thus, results from studies that have attempted to use ouabain to eliminate the contribution of the conventional Na(+) pump to volume recovery must be reevaluated if the exposure to ouabain was done in the cold or under conditions in which the Na(+) pump is not operating.     

The aggregation of reverse micelles

We have developed a computer simulation to model the formation of reverse micelles in two dimensions. Several of the qualitative results obtained from these calculations agree with experimental observations. Specifically, we have shown that the chain length has a large influence in determining the size and shape of the aggregate. We predict the existence of a critical tail length: Chains below this value will form an extended lamella-like structure, whereas chains longer than this value will form clusters that appear ellipsoid or circular in cross-section. Finally, we obtained a scaling law that relates the aggregation number (N) to the length of the tail (L):N∼L ^−1.14. A physical model to account for the observed exponent will be developed in a future paper.     

Group B Streptococci in Neonatal Deaths

Clinical microbiologists are reminded to look for group B streptococci in neonatal infants. We report four deaths, one with meningitis, occurring among 14 such infected newborn infants at our institution; of the nursing staff, 31% were also carriers of group B streptococci.