Aspirin for the older person: report of a meeting at the Royal Society of Medicine, London, 3rd November 2011.

On November 23rd 2011, the Aspirin Foundation held a meeting at the Royal Society of Medicine in London to review current thinking on the potential role of aspirin in preventing cardiovascular disease and reducing the risk of cancer in older people. The meeting was supported by Bayer Pharma AG and Novacyl.

Cerebral amyloid angiopathy in Alzheimer disease is associated with apolipoprotein E4 and cortical neuron loss.

Pathological correlations were sought between cerebral amyloid angiopathy (CAA) and other classical neurodegenerative changes in 101 consecutive cases of autopsy-confirmed Alzheimer disease (AD). Some degree of CAA was found in at least one area of the brain in 81% of the cases; severe CAA was found in at least one brain region in 29% of the cases. In a subset of 42 cases for which genomic DNA was available, greater severity of CAA was associated more with cases that were homozygous for apolipoprotein epsilon4 than in cases with only one or no epsilon4 alleles (Fisher's exact test, p = 0.005). In all brain regions, severity of CAA was inversely correlated with numbers of neurons. This correlation was statistically significant in the temporal lobe (r = -0.29,p = 0.004) and the frontal lobe (r = -0.22, p = 0.02). Our findings suggest that two factors may modify the severity of AD pathology: Apolipoprotein E4 may accentuate the vascular deposition of beta-amyloid, and severe CAA may accelerate neuronal loss.

Eligibility of Alzheimer's disease clinic patients for clinical trials.

OBJECTIVES: To identify the percentage of patients with Alzheimer's disease (AD) in a general clinic population who would be provisionally eligible for randomized clinical trials and the extent to which these patients represent the overall clinic-based population. BACKGROUND: Many randomized clinical trials have restricted enrollment criteria that may limit generalizability, i.e., AD patients who fulfill selection criteria for phase III clinical trials may not be representative of other AD patients in clinical settings. DESIGN AND SETTING: Patients diagnosed as probable or possible AD from the nine clinical sites of the State of California's Alzheimer's Disease Diagnostic and Treatment Centers (ADDTC) were selected on the basis of their provisionally fulfilling the inclusion and exclusion criteria of two typical AD clinical trials at the time of their first visit (ECG and brain imaging criteria were not available). RESULTS: From a sample of 3470 subjects with possible or probable AD, overall, only 4.4% or 7.9% would have been provisionally eligible for each of two trials. Patients provisionally eligible were younger, relatively underrepresented by women, better educated, wealthier, and more likely to be white than ineligible patients. The major independent demographic predictors for eligibility were (1) income greater than $15,000 per year, (2) male gender, and (3) college education. More than 60% of probable AD patients were excluded because of significant behavioral problems; approximately one-quarter each were excluded because of significant medical or neurological problems. Allowing patients with probable or possible AD to enroll would have resulted in 10.6% being eligible. CONCLUSION: Selection criteria for AD clinical trials result in a demographically and clinically constrained subgroup that is not representative of the overall clinic population.

Multicenter clinicopathological correlation in dementia.

OBJECTIVE: The aim of the present study was to determine the accuracy of clinical diagnoses of dementia in a large group of patients evaluated in a multicenter, university-based, Alzheimer's disease diagnostic and treatment program. METHOD: Clinical diagnoses and neuropathological results from seven collaborating Alzheimer's disease research centers were compared for 196 cases of dementia. RESULTS: When diagnoses of probable Alzheimer's disease, possible Alzheimer's disease, and Alzheimer's disease plus another condition were combined, 163 (83%) of the patients were clinically regarded as likely to have had Alzheimer's disease. Of those patients, 134 (82%) were found to have neuropathological changes diagnostic of Alzheimer's disease or Alzheimer's disease plus another condition. A total of 116 patients were diagnosed as having probable Alzheimer's disease; 100 (86%) of those were found to have pathological diagnoses of Alzheimer's disease or Alzheimer's disease plus another condition. Cerebral infarcts were found in 17% of the patients clinically diagnosed with probable Alzheimer's disease. Lewy bodies with variable Alzheimer's disease-type pathological changes were found in 7% of the patients with clinical diagnoses of probable Alzheimer's disease. Conversely, significant Alzheimer's disease-type pathological changes were found in 55% of the patients clinically diagnosed as having vascular dementia. CONCLUSIONS: Clinicians accurately predict Alzheimer's disease-type neuropathological findings in a high proportion of cases of dementia but may not predict cerebrovascular pathology and Lewy bodies in some patients with apparent clinical Alzheimer's disease and may often fail to predict Alzheimer's disease-type pathological findings in patients with apparent vascular dementia. With the emergence of effective treatments for Alzheimer's disease, there is an increasing need to optimize methods for ante-mortem diagnosis of dementia.

Extrapyramidal signs and psychiatric symptoms predict faster cognitive decline in Alzheimer's disease.

OBJECTIVE: To identify clinical predictors of cognitive decline in Alzheimer's disease. DESIGN: A cohort of patients was followed up longitudinally and the likelihood of arriving at two cognitive end points was assessed using the Cox proportional hazards model and eight explanatory variables. SETTING: Subjects were chosen from patients examined for memory loss at two medical centers affiliated with the University of Southern California, Los Angeles. PATIENTS: The sample included 135 patients who met National Institute for Neurological and Communicative Disorders and Stroke-Alzheimer's Disease and Related Disorders Association criteria for probable or definite Alzheimer's disease, had initial Mini-Mental State Examination (MMSE) scores of 14 or greater, and had been seen on at least two occasions. MAIN OUTCOME MEASURES: The time to reach either of two end points, ie, MMSE score of 8 and a decline of six points on the MMSE, was assessed. RESULTS: After controlling for initial severity of dementia (eg, by dividing the sample into mild and moderate dementia subgroups or by using the individually defined end point of a six-point decline on the MMSE), the presence at baseline of extrapyramidal signs (risk-hazard ratio, 10.34; 95% confidence interval, 2.76 to 38.68; P = .0005), agitation (risk-hazard ratio, 2.98; 95% confidence interval, 1.35 to 6.61; P = .007), and hallucinations (risk-hazard ratio, 3.85; 95% confidence interval, 1.35 to 11; P = .01) predicted a shorter time to reach an end point. CONCLUSIONS: After controlling for initial severity of dementia, the presence of extrapyramidal signs and behavioral symptoms (agitation and hallucinations) significantly predict faster cognitive decline. These findings may reflect the effects of neuroleptic medication, the presence of underlying diffuse Lewy body disease, or alterations in biogenic amine systems.

Cognitive performance in older and middle-aged depressed outpatients and controls.

Cognitive performance was assessed in older (60-75 years) and middle-aged (40-59 years) unmedicated outpatients with major depression and in healthy controls to examine potential interactive effects of age and depression. Cognitive performance was assessed from three categories of tasks: verbal, visual-spatial, and visuo-motor scanning tasks. Depressed subjects did not perform as well as controls on visuo-motor scanning tasks that included the Trail Making Tests A and B, and the Symbol Digit Modalities Test. Likewise, the older compared to the middle-aged group was slower on the visuo-motor scanning tasks. In addition, the older group showed poorer performance on visual-spatial tasks. Neither depression nor age group effects were observed for the primarily verbal tasks. Age and depression combined in an additive (noninteractive) fashion such that the older depressed subjects performed worse than the middle-aged depressed subjects, and older and middle-aged controls, on visuo-motor scanning tasks.

Predictors of differences between Type A and B individuals in heart rate and blood pressure reactivity.

Past estimates of the magnitude of Type A-B differences in cardiovascular reactivity are probably overly conservative. In addition, it is unclear which situations are more likely to elicit excessive reactivity in Type As. The present meta-analysis found that, overall, Type As had greater heart rate (mean d = .22), diastolic blood pressure (d = .22), and especially systolic blood pressure responses (d = .33) than Type Bs; these effect sizes were small but relatively consistent. However, Type As showed especially greater cardiovascular reactivity in situations characterized as having (a) positive or negative feedback evaluation, (b) socially aversive elements such as verbal harassment or criticism, and (c) elements inherent in playing video games. Measures of time urgency, Type A assessment method, and gender were not found to be strongly related to A-B differences in cardiovascular reactivity. Future studies that use more "Type A-relevant" situations will probably find greater effects.

Reliability of topographic quantitative EEG amplitude in healthy late-middle-aged and elderly subjects.

Reliabilities of quantitative measures of absolute and relative EEG amplitudes were assessed in healthy older adults under the eyes closed (n = 46) and eyes opened (n = 45) conditions. For the theta, alpha, beta 1, and beta 2 bands, reliabilities of 28 scalp derivations were stable over the 4.5 month test interval. Reliabilities of delta were lower. When appropriate transformations were applied, the reliabilities of absolute EEG amplitude measures tended to exceed those of relative measures. There were not, however, striking differences in reliabilities under the eyes closed, as compared to eyes opened condition. We concluded that when coupled with the criterion of interpretability, the generally higher reliabilities of absolute, as opposed to relative, amplitude measures render them preferable in clinical research.

Do blood pressure and age predict response to tacrine (THA) in Alzheimer's disease? A preliminary report.

Recent studies in major depression suggest that a pretreatment systolic orthostatic blood pressure (PSOP) fall of greater than or equal to 10 mm Hg in response to changing from a supine to a standing position may predict response to antidepressant treatment in older depressed patients. Because orthostatic blood pressure response is regulated, in part, by central cholinergic and noradrenergic systems, and both are implicated in Alzheimer's disease, PSOP was assessed as a predictor of initial response in Alzheimer's disease outpatients in a treatment protocol with tacrine, a cholinesterase inhibitor. We found that the magnitude of PSOP fall and increasing age each contributed to the prediction of response to tacrine. These results may suggest a relatively greater involvement of other neurotransmitter systems in younger, nonresponding Alzheimer's disease patients, and the results differ from those of a previous study.

Relationship of hydroxynortriptyline to nortriptyline concentration and creatinine clearance in depressed elderly outpatients.

Plasma concentration of E-10-hydroxynortriptyline is increased in the elderly and may be related to both renal clearance of hydroxynortriptyline and rate of liver hydroxylation of nortriptyline. In 25 ambulatory, depressed elderly outpatients treated with therapeutic doses of nortriptyline, relationships among plasma levels of nortriptyline and E-10-hydroxynortriptyline, and an estimate of creatinine clearance were examined. Plasma levels of E-10-hydroxynortriptyline (corrected for varying dosage) were significantly correlated with age and inversely correlated (r = -0.50) with creatinine clearance but not with notriptyline or Z-10-hydroxynortriptyline concentration. E-10-hydroxynortriptyline concentration was about 5 1/2 times that of Z-10-hydroxynortriptyline. By best subsets multiple regression analyses, the ratio of E-10-hydroxynortriptyline to nortriptyline level was best predicted by plasma nortriptyline concentration, creatinine clearance, and age, all of which accounted for 63% of the variance. These results corroborate and extend previous findings in elderly inpatients in whom creatinine clearance was measured directly. In addition, age had an effect on E-10-hydroxynortriptyline independently of creatinine clearance. Since E-10-hydroxynortriptyline concentration has been related to both therapeutic efficacy and toxicity during nortriptyline treatment, it may be important to assess nortriptyline hydroxymetabolites in elderly patients and in those with renal insufficiency.

A metaanalysis of controlled trials of neuroleptic treatment in dementia.

Prior qualitative literature reviews about the use of neuroleptics in dementia suggest that they are "modestly effective" in treating agitation and that no single neuroleptic is better than another. To develop a more precise concept of the clinical efficacy of neuroleptics, a metaanalytic review of the existing literature was performed. From double-blind clinical trials that compared a neuroleptic with a placebo in agitated dementia patients, P values and effect-size estimates were obtained, and were assessed by metaanalytic techniques. Results indicated that neuroleptics were significantly more effective than placebo (one-tailed P = .004) and had a small effect size (r = .18). Clinically, neuroleptic treatment changed the improvement rate in agitated dementia patients from .41 to .59 (binomial effect-size display). This indicates that 18 of 100 dementia patients benefited from neuroleptic treatment (beyond that of placebo) and is consistent with the modest efficacy described in previous qualitative reviews. In six studies comparing thioridazine with another neuroleptic, and in five studies comparing haloperidol with another neuroleptic, metaanalysis results did not show that these two medications differed significantly from the comparison medications, which is not inconsistent with the opinion that no single neuroleptic is better than another.

EEG amplitudes in healthy, late-middle-aged and elderly adults: normality of the distributions and correlations with age.

The interindividual distributions of EEG amplitudes were evaluated in 60 healthy subjects, aged 56-76. Skew and kurtosis were used to assess the normality of the amplitude distributions in 5 frequency bands (delta, theta, alpha and 2 beta ranges) and 28 scalp derivations while the subjects were awake and rested with their eyes closed and opened. Most of the interindividual EEG amplitude distributions were not normally distributed. Two transformations were applied to the EEG amplitudes: the square root and the natural logarithm. Evaluation of skew and kurtosis indicated that the natural logarithmic transformation was more effective than the square root in reducing the positive skew and leptokurtosis that characterized the untransformed interindividual EEG amplitude distributions. For all frequency bands except theta, the log transformation rendered the distributions approximately normal in form. Correlations between log transformed EEG amplitudes and age were not statistically significant. These findings are discussed in the context of previous research, aging, and methodological features.

Umbilical vein variations: review of the literature and a case report of a persistent right umbilical vein.

A case of a ligamentum teres formed from an obliterated right umbilical vein is described. It passed to the right branch of the portal vein. The quadrate and left lobes of the liver were not separated by the usual fissure. Very few cases of anomalous umbilical veins or persistent right umbilical veins have been recorded. Of these, several have been recorded only in the umbilical cord, while in others the persistent right umbilical vein has been found intra-abdominally, in an extrahepatic position, and passing directly to the right atrium or to the inferior vena cava. Its presence is generally associated with severe congenital abnormalities, in contrast with the present case. In view of the high incidence of congenital defects associated with aberrant or accessory umbilical veins, when these are detected either in the umbilical cord or in the abdomen by umbilical phlebography, it is suggested that the patient should be carefully investigated for other congenital abnormalities.

The effect of hemoglobin ligands on the kinetics of human hemoglobin A1c formation.

HbA1c is the most prevalent of the minor human hemoglobins. It is formed by the nonenzymatic addition of glucose to the alpha-amino group of the beta chain by an initial condensation reaction and a subsequent intermolecular Amadori rearrangement. We have developed a method of analysis which utilizes high performance liquid chromatography to follow the formation of HbA1c and greatly simplifies the determination of the kinetic parameters associated with this reaction. This has allowed us to study the effects of several Hb ligands, including the hydrogen ion, on the kinetics of this glycosylation reaction. Both the initial condensation reaction and the subsequent rearrangement are shown to exhibit acid catalysis, but the rate of the condensation step is limited by the extent of protonation of the alpha-amino group. The variation in kinetic parameters as a function of hydrogen ion concentration has allowed us to determine the probable reaction mechanism of HbA1c formation by comparison to previously reported model systems of Schiff base formation and Amadori rearrangement. The formation of pre-HbA1c from deoxy-Hb shows an increased forward rate when compared to oxy-Hb. The presence of physiologic concentrations of CO2 causes a proportional decrease in both k1 and k-1. 2,3-Diphosphoglycerate causes a significant increase in the keq of the formation reaction. The effects of CO and the substitution of L-glucose for D-glucose are not significant.

Vascular complications of upper cervical spine injuries.

Upper cervical spine injuries can be complicated by occlusion of the vertebral and carotid arteries. Injury to the former is more common. The arteries may be kinked or temporarily occluded, in which case the symptoms are transient. With more forceful trauma, damage to the intima and subsequent thrombosis or prolonged spasm may ensue. Early recognition of ischemic symptoms hastens the diagnosis. In most instances it is not possible to alter advanced neurologic deficits once they are established.