Review article

Genetics of dementia

The ageing population is both a marvel of civilisation and a huge challenge for healthcare provision. Coupled with surgical and anaesthetic advances, this shift in population distribution has meant that far greater numbers of elderly patients are undergoing surgery than has ever previously been the case. This is a double edged sword as the elderly population are more prone to develop perioperative complications than younger patients.

Postoperative cognitive dysfunction (POCD) is one such complication, and can result in a serious deterioration in quality of life and an increased duration of hospital stay. It may persist for months or even years, and could yet prove to be a harbinger for the development of dementia in later life.

The pathogenesis of POCD is still not yet fully understood, though a number of mechanisms have been postulated and there are several clearly identified risk factor. POCD also does not yet have a standardised diagnostic classification, and this has proven problematic in terms of research progress. Unsurprisingly, the complex relationship between POCD and dementia has also yet to be fully elucidated, though there is considerable overlap in risk factors for the two conditions.

The common theme that runs through the risk factors for POCD is that they all pertain to either a reduction in functional reserve or a propensity to cerebral injury. Many of these risk factors are non-modifiable such as age, genotype, history of cerebrovascular disease and preoperative cognitive function. One exception to this is the development of postoperative delirium, which may also increase the risk of POCD. Postoperative delirium has myriad potential causes, many of which are treatable, if not preventable. This makes postoperative delirium an interesting prospect for study, as if it does contribute to the development of POCD then its early detection and management could produce real improvements in quality of life for many elderly patients.

This review will outline the existing theories as to the pathophysiology underpinning POCD, the problems in defining it and the merits of various methods used in its detection. Risk factors precluding the development of POCD will also be discussed, with a focus placed specifically on age, preoperative cognitive status and the role of postoperative delirium. Common causes of postoperative delirium and their potential as modifiable risk factors will be highlighted and the protective or deleterious roles of common anaesthetic agents, type of surgery and certain individual factors will also be examined. Finally, the authors have offered some general principles of good practice to guide management in lieu of more concrete, targeted recommendations.

Neurodegenerative diseases are a major health concern worldwide. Diseases such as Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis, as well as many other diseases affecting the neuromuscular system, are a leading cause of disability in the aging population. Presymptomatic diagnosis of neurodegenerative disorders is challenging due to the lack of robust biomarkers. Likewise, the design of effective intervention strategies is limited because most neurodegenerative disorders are heterogeneous in nature. Reliable noninvasive biomarkers are therefore urgently needed to allow presymptomatic and accurate diagnosis, to track disease progression, to evaluate the effectiveness of new treatment regimens, and to ultimately design new therapeutic intervention strategies. Recent biological and technological advances within the field of proteomic promises to provide insight into global proteome changes in neurodegeneration, thus allowing increased understanding of molecular pathways leading to neuronal cell death and the identification of biomarkers. The combination of gel-based techniques and mass spectrometry permits large-scale identification of peptide sequences in biological samples as well as the characterization of posttranslational protein modifications. The application of comparative high-throughput proteomic analyses in animal models and human tissues will aid in the identification of both diagnostic and prognostic biomarkers and will provide a platform for a future personalized medicine approach in neurodegeneration.

Advances in our understanding of the etiologies and pathogenesis of Alzheimer's disease (AD) highlight a role for free radical-mediated injury to brain regions from early stages of this illness. Here we will review the evidence from transgenic mouse models of AD, autopsy samples, and human biofluids obtained during life paying particular attention to the stage of disease. In addition, we will review the epidemiologic literature that addresses the potential of anti-oxidants to prevent incident dementia from AD, and the clinical trial literature that addresses anti-oxidant preventative or therapeutic strategies for different stage of AD. Future efforts in preclinical models and ultimately clinical trials are needed to define optimally effective agents and combinations, doses, and timing to suppress safely this facet of AD.

Parkinsonism-dementia complex (PDC) remains a significant health burden to the Chamorro population. We tested the hypothesis that quantitative proteomics might provide fresh insight into this enigmatic illness by analyzing proteins resistant to surfactant extraction from patients with Alzheimer's disease (AD) or PDC and their matched controls using isobaric tags for relative and absolute quantification. In addition to the expected increase in abnormal frontal cortical Aβ peptides, tau, ubiquitin, and apolipoprotein E in AD, and tau in PDC, we identified α-synuclein (SNCA) as a major abnormal protein in PDC but not AD. We confirmed our isobaric tags for relative and absolute quantification findings by enzyme-linked immunosorbent assay in frontal and temporal cortices. We extended our assays to include a limited number of cases of progressive supranuclear palsy (PSP) and dementia with Lewy bodies; we observed increased abnormal tau but not SNCA in PSP, and abnormal SNCA in dementia with Lewy bodies that was quantitatively similar to PDC. Finally, soluble Aβ oligomers were selectively increased in AD but not PDC or PSP. These results show that frontal and temporal cortex in PDC is distinguished from AD and PSP by its accumulation of abnormal SNCA and suggest that PDC be considered a synucleinopathy as well as a tauopathy.

Whether patients who subsequently develop early postoperative delirium have a genetic predisposition that renders them at risk for postoperative delirium has not been determined.

The authors conducted a nested cohort study to include patients aged ≥ 65 yr who were scheduled to undergo major noncardiac surgery requiring anesthesia. A structured interview was conducted preoperatively and for the first 2 days postoperatively to determine the presence of delirium, defined using the Confusion Assessment Method. Blood was drawn for measurement of the apolipoprotein genotypes. Bivariate tests of association were conducted between delirium and apolipoprotein genotypes and other potentially important risk factors. Variables that had significant bivariate association with postoperative delirium were entered in a forward multivariable logistic regression model.

Of the 190 patients studied, 15.3% developed delirium on both days 1 and 2 after surgery. Forty-six patients (24.2%) had at least one copy of the apolipoprotein e4 allele. The presence of one copy of the e4 allele was associated with an increased risk of early postoperative delirium (28.3% vs. 11.1%; P = 0.005). Even after adjusting for covariates, patients with one copy of the e4 allele were still more likely to have an increased risk of early postoperative delirium (odds ratio, 3.64; 95% confidence interval, 1.51–8.77) compared with those without the e4 allele.

Apolipoprotein e4 carrier status was associated with an increased risk for early postoperative delirium after controlling for known demographic and clinical risk factors. These results suggest that genetic predisposition plays a role and may interact with anesthetic/surgical factors contributing to the development of early postoperative delirium.