Online newspaper of professor Yasser Metwally

The author: Professor Yasser Metwally

http://yassermetwally.com

INTRODUCTION

August 30, 2008 — As people grow older, they experience a substantial acceleration in cognitive decline — even if they don’t have dementia, a new study suggests.

“Based on previous studies, we expected to see an acceleration in the decline in cognitive abilities before death,” said lead author Valgeir Thorvaldsson, MSc, from the department of psychology at Göteborg University, in Sweden. “However, the onset of this acceleration was much earlier than we expected.”

Mr. Thorvaldsson said this was especially the case for perceptual speed, where the average onset of terminal decline was almost 15 years before death.

“The findings imply that the brain changes that influence cognitive abilities in old age occur over a relatively long period of time,” he noted.

Their findings were published online August 27 in Neurology.

• Rate of Change

In this investigation, the researchers wanted to identify the time of onset and rate of mortality-related change in cognitive abilities in later life. They studied 288 people in Göteborg who were born in 1901 and 1902. The individuals, who did not have dementia, were followed from age 70 until death.

Investigators tested participants on 3 cognitive abilities — verbal skills, spatial ability, and perceptual speed. They performed change-point analyses using an automated piecewise linear mixed-modeling approach. The group used this to identify the inflection point indicating accelerated within-person change related to mortality.

The researchers point out that the terminal decline phases in their work were considerably longer than estimates from similar studies. “One study found evidence for terminal decline 3.33 years before death in semantic memory, 6 years in visuospatial ability, and only 2.75 years in perceptual speed,” they note (Neurology. 2003; 60:1782-1787).

Another study they cite found a terminal decline phase on episodic memory ranging over 8.4 years before death (Eur Psychol. 2006;11:172-181). “Our findings for both verbal ability and spatial ability are similar to this estimate, but our estimate for perceptual speed is much longer,” note the researchers.

Measures of processing speed are typically one of the most sensitive markers of age-related change and between-person age differences, they point out. “Our finding that speed was the earliest marker of mortality-related decline is in line with these findings.”

Neurobiological Markers for Terminal Decline Unknown

There are a number of factors that might explain these findings, note the researchers. Cardiovascular conditions and undetected preclinical dementia are 2 examples.

Increased medical burden and frailty in old age often lead to inactivity and a lack of physical exercise and cognitive stimulation, which can accelerate decline. “Subsequent studies need to illuminate these issues and identify the neurobiological markers for terminal decline,” they note.

“One of the limitations to this longitudinal study that started more than 35 years ago is that we do not have detailed information about brain pathology from brain scans or indexes of biomarker from cerebrospinal fluids,” Mr. Thorvaldsson explained.

“Another limitation that critics might address is that our tests didn’t cover all cognitive domains; for example, episodic memory known to be highly sensitive for change in aging and in various diseases,” he added.

Mr. Thorvaldsson recommends additional study to identify the causes of the problem and to find methods to prevent or treat decline. Because, he noted, “we know how important intact cognitive capabilities are for well being and everyday-life functioning in old age.”

References

1. Neurology. Published online August 27, 2008.

The author: Professor Yasser Metwally

http://yassermetwally.com

INTRODUCTION

August 30, 2008 — Acute maternal stress in the second month of pregnancy significantly increases the likelihood that the child will develop schizophrenia in later life, particularly if that child is female.

Investigators at the New York University School of Medicine, in New York, found that acute maternal stress in the second month of pregnancy was associated with a 2.3-fold increased risk for schizophrenia in children; the risk was more than 4-fold among female children.

According to principal investigator Dolores Malaspina, MD, MPH, schizophrenia has been linked with intrauterine exposure to maternal stress due to bereavement, famine, and major disasters, and recent evidence suggests that humans are most vulnerable in the first trimester of gestation.

“We showed that severe stress alone, in the absence of infection, malnutrition, or environmental changes, is related to later schizophrenia. Furthermore, we were able to pinpoint the timing of this risk, and showed there was sex specificity and that female offspring are at much greater risk than males,” said Dr. Malaspina .

• Natural Experiment

Until recently, the evidence has been limited by low statistical power. The researchers note that it has been difficult to separate short-term psychic stressors from the long-term influence of disrupted environments, diets, or lifestyles that can act as chronic stressors during childhood. Furthermore, earlier research lacked specificity regarding the timing of stress and its character.

To examine the consequences of acute maternal stress in children, the investigators followed a cohort of offspring whose mothers were pregnant in June 1967, during the 6-day Arab–Israeli war.

This conflict, said Dr. Malaspina, was extremely severe but relatively short-lived, so provided investigators with “a natural experiment.”

The researchers linked birth records with Israel’s Psychiatric Registry and then analyzed data from the Jerusalem Perinatal Study, a population-based research cohort of 88,829 individuals born in Jerusalem between 1964 and 1976.

“We looked at the timing of the individuals’ birth to narrow down, month by month, the exact point [in their gestational life] the insult took place, and then correlated that information with a diagnosis of schizophrenia in later life,” said Dr. Malaspina.

• Survival Effect?

A total of 637 people in this cohort of 88,829 were identified with schizophrenia-related diagnoses, and 676 were identified with other psychiatric disorders. According to the study, the raw data suggest a 2- to 3-fold excess of schizophrenia in the cohort born in January 1968, whose mothers would have been in their second month of pregnancy in June 1967.

The researchers found no unusual incidence of schizophrenia or other conditions among children conceived in the 3 months after the war, or in those born in the 3 months before it.

Adjusted analyses revealed that the overall incidence of schizophrenia was more than double that for children who were in the second month of gestation in June 1967. In males alone, there was a 20% increased risk for the disorder; in females, the hazard ratio was 4.3.

The reason for the higher incidence of schizophrenia among females is not clear. But there are at least 2 potential hypotheses. The first is that males are less susceptible to schizophrenia, study coauthor Susan Harlap, MBBS, said in an interview.

However, she said, there is a second, and possibly more likely, explanation. Animal and clinical research shows that severely stressed females frequently spontaneously abort. In addition, epidemiologic studies show that male fetuses tend to be miscarried more frequently than females.

“There may be a survival effect at play, so it is not necessarily that female fetuses are more susceptible to schizophrenia due to maternal stress, but that they are less likely to be aborted in the presence of maternal stress,” said Dr. Harlap.

• Tip of the Iceberg?

According to Dr. Malaspina, the study’s findings underscore the potential negative impact of maternal stress on the developing fetus.

“Severe stress may just be the tip of the iceberg. We must keep in mind that the brain doesn’t develop from a blueprint, and stress during pregnancy can program genes for many medical conditions,” she said.

Physicians need to advise women who are planning a family to reduce their stress levels well in advance of the actual pregnancy, she added.

“I believe there’s very little information given to pregnant women about the need to reduce stress well before and during pregnancy. A certain amount of maternal stress is absolutely necessary for healthy fetal development, but women should be advised to, as much as they can, lead a healthy life that includes exercise, proper sleep, good nutrition, and reduced stress. We want all our patients to live a healthy lifestyle, and here’s 1 more reason to,” said Dr. Malaspina.

References

1. BMC Psychiatry. 2008; Published online before print August 21, 2008. Abstract

The author: Professor Yasser Metwally

http://yassermetwally.com

INTRODUCTION

August 15, 2007 — Coffee drinking, but not cigarette smoking, may have a protective effect in primary late-onset blepharospasm, a form of focal adult-onset dystonia.

Investigators at the University of Bari in Italy found individuals who drank 1 to 2 cups of coffee per day were less likely to develop the condition than those who drank less than this amount. Furthermore, there was a delay in the age of onset of the condition associated with coffee consumption — 1.7 years for each additional cup per day.

However, unlike studies of Parkinson’s disease, which have linked smoking to a decreased risk for the disease, as well as in a previous study of blepharospasm, the Italian team found no significant protective effect of blepharospasm related to cigarette smoking.

“The protective effect of cigarette smoking and coffee in Parkinson’s disease is well established. However, there is a paucity of information on the role of these lifestyle habits in BSP, a condition that, like PD [Parkinson’s disease], is thought to arise,”said principal investigator Giovanni Defazio, MD, of the University of Barin

The study is published in the June 19 Online First issue of the Journal of Neurology, Neurosurgery, and Psychiatry.

• Smoking Conferred No Protective Effect

In this retrospective, case-control, multicenter study, the 2 lifestyle habits, coffee drinking and cigarette smoking, were examined in 166 patients with primary late-onset blepharospasm, 187 healthy population control subjects (patients’ relatives), and 228 hospital control patients with primary hemifacial spasm all from 5 hospital-based movement disorder clinics in Italy.

The lifetime coffee consumption and smoking habits were determined for all participants by an expert interviewer who was not blinded to the case/control status but was unaware of the study hypothesis. All study subjects were asked about their coffee and smoking habits up to the reference age. This was the age of onset of dystonia or hemifacial spasm for case patients and hospital control patients.

A reference age was calculated for the population control subjects based on the duration of the spasms in the hospital control patients.

Study participants were also asked to estimate how many cups of coffee they drank and/or packs of cigarettes they smoked per day. Demographic and clinical information was also collected.

The investigators found that individuals with blepharospasm reported a significantly lower mean number of cups of coffee per day than hospital control patients and population control subjects, whereas there was no significant relationship with the amount smoked per day and a reduced risk for blepharospasm.

• Delayed Disease Onset

“We found patients with blepharospasm drank coffee less often than controls. The other important result was the observation that for every additional cup of coffee consumed per day there was a delay in the age of onset of blepharospasm. Both findings support a protective effect. Nevertheless, methodologically robust studies in independent populations are needed to confirm this hypothesis,” he said.

According to Dr. Defazio, prevalence estimates of blepharospasm are uncertain. Available studies, he said, are biased because of a number of methodologic problems and likely provide an underestimation. However, he said, the most relevant research showed a prevalence of about 133 per 1 million population. Dystonia in general, he added, affects approximately 1000 per million population.

The protective effect associated with coffee is most likely caffeine, said Dr. DeFazio.

“The association of caffeine and BSP [blepharospasm] may be biologically plausible given the pro-dopaminergic activity exerted by caffeine through an antagonistic action on adenosine receptors. This has been called into play to explain the observed protective effect on the development of PD. Likewise, a relative hypodopaminergic status has been proposed in the pathophysiology of BSP,” the authors write.

As a result, said Dr. Defazio, adenosine receptor antagonists may effectively alleviate blepharospasm symptoms.

The team’s next research steps, said Dr. Defazio, will be to determine whether coffee consumption has any protective effect in other forms of dystonia such as writer’s cramp and cervical dystonia, because although these conditions differ in their clinical presentations, it is likely they have a common etiology.

“I believe our data may have implications for the understanding of the etiology and treatment of primary BSP and that future studies seeking additional environmental or genetic factors for dystonia should take the effect of coffee into account,” he said.

• Clinical Context

According to the authors of the current study, blepharospasm is a common late-onset dystonia that is probably related to a combination of genetic and environmental factors. Like Parkinson’s disease, there may be an association between smoking and blepharospasm onset. Caffeine has a dopaminergic effect, according to the authors, and it is biologically plausible that caffeine may exert a protective effect against blepharospasm via an antagonistic action on adenosine receptors, because a relative hypodopaminergic status has been proposed as the pathophysiology of blepharospasm.

This is a retrospective case-control study to examine the role of lifetime coffee consumption and cigarette smoking on the risk for primary blepharospasm.

• Study Highlights

  1. 166 outpatients with blepharospasm were recruited from 5 Italian centers for 12 months: 131 with focal blepharospasm and 35 with blepharospasm as part of a segmental dystonia.

  2. Case patients were matched by age, sex, and center to 228 patients with primary hemifacial spasm and 187 patients’ relatives, both attending participating centers during the study period.

  3. The case patients thus were compared with an inpatient and a population-based cohort of controls.

  4. Case patients and controls were unaware of the study hypothesis.

  5. A trained interviewer asked patients, “Have you ever drunk non-decaffeinated coffee or smoked cigarettes?”

  6. Those who responded “yes” were asked when they began and whether they quit before the reference age.

  7. The reference age was the age of onset of dystonia or hemifacial spasm.

  8. The average years of coffee drinking/smoking and daily number of cups drank or cigarettes smoked (1 pack = 20 cigarettes) were determined.

  9. A test-retest study was performed 1 year after the first interview in a subset of participants, to examine the reliability of recall, for 33 case patients and 34 hospital control patients.

  10. Case patients and hospital control patients in the repeatability substudy showed high repeatability in recalling age of disease onset, coffee status, and smoking status including number of cups and packs per day.

  11. Mean age was 65 to 67 years, there were more women than men, and case patients were less educated than hospital control patients and population control subjects.

  12. 4% of case patients, 4% of hospital control patients, and 5% of population control subjects were past coffee drinkers.

  13. 15% of case patients, 22% of hospital control patients, and 17% of population control subjects were past smokers.

  14. Univariate analysis showed a significant inverse relationship between ever coffee drinking and cigarette smoking and blepharospasm.

  15. Multivariate analysis showed an inverse relationship with coffee drinking but not cigarette smoking.

  16. Patients with blepharospasm reported a significantly lower mean number of cups of coffee per day vs hospital control patients and population control subjects (1.8 vs 2.32 vs 2.44 cups per day, respectively; P < .0001).

  17. The odds ratio for coffee intake and blepharospasm comparing case patients and hospital control patients was 0.37 (95% confidence interval, 0.20 – 0.67) and comparing case patients and population control subjects was 0.44 (95% confidence interval, 0.23 – 0.85).

  18. The strength of the association increased with the amount of coffee drank in numbers of cups per day.

  19. There was a significant correlation between age of blepharospasm onset and number of cups per day (adjusted regression coefficient, 1.73; P = .001).

  20. There was no significant interaction between coffee drinking and smoking cigarettes.

  21. The authors concluded that coffee drinking may be inversely related to onset of blepharospasm and that this association may be dependent on the amount of coffee consumed.

  22. The authors recommended that the effect of coffee should be considered when seeking additional environmental factors associated with blepharospasm.

• Pearls for Practice

  1. Smoking cigarettes is not associated with blepharospasm.

  2. There is an inverse association between coffee drinking and blepharospasm, with higher consumption levels increasing strength of the association

References

1. J Neurol Neurosurg Psychiatry. Published online June 19, 2007..

The author: Professor Yasser Metwally

http://yassermetwally.com

INTRODUCTION

August, 2008 — A new study suggests that combination therapy with insulin and other oral antidiabetes drugs is associated with a significant reduction in the density of neuritic plaques in the brains of people with type 2 diabetes.

The postmortem study compared plaques and neurofibrillary tangles in the brains of people with and without type 2 diabetes who were matched for age at death, sex, and severity of dementia. They report that those taking the combination of insulin and other oral antidiabetic drugs had significantly fewer plaques than those taking either type of medication alone and those taking no medication, although there was no difference in the number of tangles between groups.

Michal Schnaider Beeri, MD, from the Mount Sinai School of Medicine, in New York, New York, cautioned that their results show only an association and don’t prove causation. “But assuming that those results hold (and they are quite robust), this also points to biologic pathways in the brain, such as the insulin-receptor-signaling pathway, that might be a focus for developing new treatment strategies for Alzheimer’s disease in the future.”

Their findings were presented here at ICAD 2008: Alzheimer’s Association International Conference on Alzheimer’s Disease.

• Discrepant Findings

Epidemiologic studies have found a stronger association with risk for cognitive decline, mild cognitive impairment, and dementia — both Alzheimer’s disease and vascular dementia — in those with type 2 diabetes than in those without diabetes, Dr. Beeri said.

However, the increased risk for dementia seen in those with type 2 diabetes has not been borne out by increased neuropathology in the brain, she said. “Studies of the brain have found either no relation or a reverse relation between diabetes and brain lesions,” she noted. In their own previous work, for example, they examined brain samples from people with and without diabetes from the Mount Sinai Brain Bank and found, contrary to their hypothesis, that the association with AD neuropathology, including neurofibrillary tangles and neuritic plaques, was weaker in people with than without type 2 diabetes.

One possible explanation for this discrepancy between the epidemiologic and neuropathologic studies is the effect of diabetes medications in reducing AD neuropathology in diabetes patients, Dr. Beeri said.

In the study presented here, the researchers again used brain samples from the Mount Sinai Brain Bank, comparing brains from 124 people with type 2 diabetes and 124 people without diabetes matched for age at death, sex, and severity of dementia.

Lifetime medications were recorded for the diabetic subjects: 29 were taking no medication, 49 were taking insulin only, 28 were taking antidiabetes medications other than insulin, and 18 were taking a combination of insulin and another antidiabetes medication.

They compared the numbers of plaques and tangles in the hippocampus, entorhinal cortex, amygdala, and in 5 regions of the cerebral cortex expressed as a summary score. Their results were consistent across all of these brain regions, she said. “The combination-therapy group had on average 80% fewer neuritic plaques than the other groups, but those other 4 groups were not statistically different from each other,” Dr. Beeri said.

Surprisingly, she added, no differences were seen in the density of neurofibrillary tangles between the groups.

Dr. Beeri said that according to the Clinical Dementia Rating (CDR) scores of these patients, the majority had dementia, despite the reduced number of plaques associated with treatment with the combination of insulin and other diabetes medications, a finding that was disappointing and is difficult to explain. However, she noted, the CDRs were established postmortem, through interviews with the families and doctors of these patients.

“It’s really difficult to extrapolate 1 postmortem CDR [score] to the real cognitive condition of the person,” she said. The finding, though, was mirrored recently by a finding reported in the Lancet, showing that immunization against the amyloid-ß peptide (Aß42) cleared amyloid plaques but did not prevent progression to severe dementia or improve survival (Holmes C et al. Lancet 2008;372:216-223). “It may be that that’s the truth, but I just really don’t think that’s the case,” she said.

Their group is now pursuing 2 more studies to provide insight into this relationship, she noted. In 1 study, they hope to use data from a health management organization (HMO) in Israel. The nature of the healthcare system in that relatively small country means that detailed longitudinal information is available and that the effects of specific medications and combinations of medications on cognition in a large cohort of patients with diabetes can be examined.

In a second study, they plan to look in a more basic way at protein and gene expression in the insulin-receptor-signaling pathway in the same brains they used in their current study. “Our hypothesis is that the gene and protein expression of those people on combination therapy is going to be normalized,” she said.

• Intriguing Findings

Asked to comment on these findings, Ralph A. Nixon, MD, PhD, professor of psychiatry and cell biology at New York University School of Medicine, in New York, and a spokesperson for the Alzheimer’s Association, called the findings, “very intriguing, because the linkage between diabetes and AD is something that’s been bandied about for some time now, and [we've been unable] to make a connection that’s really conclusive,” he said.

“This study is pretty interesting because the neuropathology is a pretty hard marker of a change, and this association between the 2 drugs being administered together and such a significant reduction in plaque load, I think, is a very hard piece of data,” he said. Obesity is currently epidemic and leads often to type 2 diabetes, Dr. Nixon added. “If we could reduce the incidence of Alzheimer’s disease in that population by combining these drugs, I think that would be something certainly worth following up. [We need to look] much more closely at diabetes as a risk factor for AD pathology and probably AD itself.”

He agreed that the fact that many of those taking the combination therapy had dementia despite a reduced number of plaques, along with the recent findings on amyloid-ß immunization, underlines a possible disconnect in the role of AD neuropathology and cognitive deficits. “I think this is something now in the field that is going to have to be aggressively investigated. What manifestation in the brain is most predictive of the dementia or memory deficits?” he said.

There are currently 2 views on this, he added. One hypothesis is that those who have pathology but don’t have symptoms are about to develop them or will at some point in the future. The other is that there is be a subpopulation who, despite the presence of the neuropathology, have some unknown resistance factor that allows them to withstand the damage without symptoms.

“So it’s an interesting time in the field, because plaques and tangles have been the hallmarks. But it’s always been a question whether they are a marker of dementia or just some sort of indirect indication of memory deficit,” Dr. Nixon said.

References

1. ICAD 2008: Alzheimer’s Association International Conference on Alzheimer’s Disease: Abstract O2-04-01. Presented July 28, 2008.

The author: Professor Yasser Metwally

http://yassermetwally.com

INTRODUCTION

August 14, 2008 — Current smokers have increased platelet inhibition and lower platelet aggregation on clopidogrel than nonsmokers, a new study has shown [1]. The authors say that the mechanism of this smoking effect deserves further study and may be an important cause of response variability to clopidogrel therapy.

The study, published in the August 12, 2008, issue of the Journal of the American College of Cardiology (online August 4), was conducted by a group led by Dr Kevin Bliden (Sinai Center for Thrombosis Research, Baltimore, MD).

Senior author Dr Paul Gurbel (Sinai Center for Thrombosis Research) commented: “We had a hint of this reaction before, as a previous study we conducted in 96 patients treated with 300 mg of clopidogrel for elective coronary artery stenting showed that 28% of the responders to clopidogrel were smokers, compared with 13% of the nonresponders. And another study by Matetzky et al has reported that smokers were less often clopidogrel resistant.”

• Explains effect of smoking seen in CREDO

“We didn’t really make much of our earlier observation, as it was such a small study, but then there was an abstract presented at the ACC [American College of Cardiology] in 2006 suggesting that smoking appeared to influence the clinical effect of clopidogrel in the CREDO [Clopidogrel for the Reduction of Events During Observation] study, with a larger reduction in clinical events seen with the drug in smokers than in nonsmokers. And there has subsequently been an analysis of the CLARITY [PCI-Clopidogrel as Adjunctive Reperfusion Therapy] trial showing a similar observation. This gave us the interest to look further at our data set,” Gurbel said. He added that smoking has also been shown to induce the cytochrome P1A2 (CYP1A2) enzyme, which converts clopidogrel to its active metabolite.

His team therefore analyzed platelet-function data in 259 patients (104 smokers and 155 nonsmokers) undergoing elective percutaneous coronary intervention (PCI) treated with clopidogrel consecutively enrolled in clinical trials at their hospital. Previous smokers were excluded. Of the patients included, 120 were on chronic clopidogrel therapy and were not loaded and 139 were clopidogrel naive and were loaded with 600 mg. Adenosine diphosphate (ADP)-stimulated platelet aggregation was assessed by conventional aggregometry and the ADP-stimulated total and active glycoprotein (GP) IIb/IIIa expression were assessed with flow cytometry.

Results showed that smokers on chronic clopidogrel therapy displayed significantly lower platelet aggregation and ADP-stimulated active GP IIb/IIIa expression compared with nonsmokers (p<0.0008 for both). Similarly, current smokers treated with 600 mg of clopidogrel displayed greater platelet inhibition and lower active GP IIb/IIIa expression compared with nonsmokers (p<0.05). In a multivariate Cox regression analysis, current smoking was an independent predictor of low platelet aggregation (p=0.0001).

• Upregulates conversion to active metabolite

Gurbel commented: “Although there have already been some data suggesting that smoking may affect the response to clopidogrel, our findings show that this can be translated into an antiplatelet effect.” Noting that clopidogrel has to be activated by cytochrome P450 enzymes, which produce the active metabolite, and that smoking induces one of these enzymes, Gurbel added: “We think that smoking upregulates this pathway.” He noted that many other agents that can modulate P450 activity may have an effect on the amount of clopidogrel active metabolite produced. These include Saint John’s wort, which also upregulates the pathway, and omeprazole, which competes for the site on the P450 enzymes and therefore slows production of the clopidogrel active metabolite.

Gurbel said that it is not possible to make any clinical recommendations on altering the dose of clopidogrel in smokers or nonsmokers on the basis of these data. “Our trial is not a prospective study, and while we believe our observations are real, they are not enough to base clinical decisions on,” he said. “In addition, the effect of smoking will probably not be a simple formula, as its influence will differ from one individual to another. I certainly do not suggest people start smoking to get an increased effect from clopidogrel. Rather, this study highlights the limitations of using a prodrug that needs to be metabolized to exert an antiplatelet effect and suggests that a direct-acting antiplatelet agent would make more sense,” he added.

This study was sponsored by Daiichi Sankyo, the maker of the competing antiplatelet agent prasugrel. Two of the authors are employees of Daiichi Sankyo. Dr. Gurbel has received grant support from Daiichi Sankyo, AstraZeneca, Schering Plough, Portolo, Bayer, and sanofi-aventis.

• Clinical Context

Clopidogrel is a prodrug that is metabolized in the liver in 2 steps to its active metabolite. The active metabolite binds irreversibly to platelet receptors to inhibit platelet aggregation. However, patients with highly reactive platelet receptors have been demonstrated to have higher rates of ischemic events after PCI.

Cigarette smoking induces one of the CYP450 enzymes that metabolize clopidogrel into its active metabolite, and there is some evidence that smokers have better cardiovascular outcomes with clopidogrel treatment vs nonsmokers. The current study compares platelet inhibition with clopidogrel therapy in smokers and nonsmokers.

• Study Highlights

  1. All study participants were undergoing PCI in 1 treatment center.

  2. Current cigarette smoking was defined as smoking within 2 weeks of PCI, and nonsmokers had not smoked within 1 year of PCI.

  3. Only patients who were naive to treatment with clopidogrel received a loading dose of clopidogrel after PCI.

  4. The main outcomes of the study were measures of platelet aggregation, including conventional aggregometry and ADP-stimulated total and active GP IIb/IIIa expression. All participants had these tests performed before PCI as well as at 18 to 24 hours after PCI (in subjects who were not treated with eptifibatide) or at 5 or more days after PCI (in subjects who received eptifibatide).

  5. 104 cigarette smokers were compared with 155 nonsmokers. Demographic characteristics were similar between the 2 groups, although smokers had higher rates of previous myocardial infarction and treatment of bifurcation lesions. Nonsmokers had higher rates of diabetes vs smokers.

  6. Current smokers had reduced platelet aggregation while receiving long-term clopidogrel therapy vs nonsmokers, as measured by 5 and 20 µmol/L ADP-induced platelet aggregation as well as ADP-stimulated active GP IIb/IIIa expression.

  7. Smokers also experienced reduced greater platelet aggregation after a loading dose of clopidogrel vs nonsmokers.

  8. Smoking at least 1 half-pack of cigarettes daily was associated with reduced platelet aggregation with clopidogrel therapy. Lower levels of smoking conferred no benefit.

  9. Researchers analyzed whether other factors could also affect platelet aggregation with clopidogrel, including age, body mass index, diabetes, and the use of other cardiovascular medications. Only cigarette smoking significantly altered the efficacy of clopidogrel in platelet inhibition.

• Pearls for Practice

  1. Clopidogrel is a prodrug that is metabolized in 2 steps with CYP450 enzymes. The active metabolite of clopidogrel binds irreversibly to platelet receptors to inhibit platelet aggregation. However, patients with highly reactive platelet receptors have been demonstrated to have higher rates of ischemic events after PCI.

  2. The current study demonstrates that platelet aggregation is more inhibited among smokers vs nonsmokers who are treated with clopidogrel.

References

1. Bliden KP, DiChiara J, Lawal L, et al. The association of cigarette smoking with enhanced platelet inhibition by clopidogrel. J Am Coll Cardiol. 2008;52:531-533.

The author: Professor Yasser Metwally

http://yassermetwally.com

INTRODUCTION

August 1, 2008 — Optic nerve head drusen are seen in approximately 1% of the population and may be bilateral in 70% of cases; caucasians are affected preferentially, and inheritance may be autosomal dominant, with incomplete penetrance. They occur as a result of retained hyaline bodies in the optic nerve head and often become calcified after adolescence and then are detected easily with ultrasound or CT (Fig. 1). Patients often are asymptomatic, and they may be an incidental finding but are a major cause of psuedopapilloedema.

Figure 1. Axial CT. Small bilateral hyperdense lesions at the optic nerve heads are shown incidentally and are typical of calcified drusen. (Click to magnify figure)

Some patients, however, may experience mild reduction in visual acuity and arcuate scotomas, sectoral field loss, and altitudinal defects. Patients also may be at increased risk for developing nonarteritic anterior ischemic optic neuropathy or branch and central retinal vein occlusion. Occasionally, a small new area of blood vessels develops as a choroidal neovascular membrane adjacent to the optic disc, which can bleed and result in visual loss. Patients who have optic nerve head drusen need clinical follow-up.

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References

1. Metwally, MYM: Textbook of neuroimaging, A CD-ROM publication, (Metwally, MYM editor) WEB-CD agency for electronic publication, version 9.2a April 2008 [Click to have a look at the home page]

The author: Professor Yasser Metwally

http://yassermetwally.com

INTRODUCTION

August 1, 2008 — A low level of high-density lipoprotein cholesterol (HDL-C) in middle age is associated with poor memory, and could lead to dementia later in life, a new study suggests [1].

In the current study, lower levels of HDL-C were associated with higher rates of memory deficit and memory decline, but total cholesterol and triglyceride levels did not have a significant effect on memory.

The study, published in the July 1, 2008 issue of Arteriosclerosis, Thrombosis and Vascular Biology, was conducted by a team led by Dr Archana Singh-Manoux (INSERM, Villejuif Cedex, France).

They explain that there is some evidence suggesting that dementia itself modifies lipid levels, leading to low total-cholesterol or low-density lipoprotein cholesterol (LDL-C) levels among those with dementia, so examination of the effect of lipids on cognition in the elderly is likely to yield spurious results. They add that associations between mid-life lipid levels and late-life dementia appear to be robust, although the precise lipid level that might be important is unclear; some studies have implicated high levels of LDL-C or total cholesterol, whereas others have implicated low levels of HDL-C. They note that HDL-C is critical for the maturation of synapses and the maintenance of synaptic plasticity; it can influence the formation of amyloid, the major component of the protein plaques found in the brains of Alzheimer’s patients. Low HDL-C has also been shown to be associated with lower hippocampal volume.

In the current study, the researchers investigated the association between lipids and short-term verbal memory in 3673 participants in the Whitehall II study, a long-term health examination of more than 10,000 British civil servants working in London, UK. They measured total cholesterol, HDL-C, and triglycerides, and assessed short-term memory at two time points: first between 1995 and 1997, when participants had a mean age of 55 years; and again between 2002 and 2004, when participants had a mean age of 61 years. Memory was assessed using 20 one- or two-syllable words read aloud at two-second intervals. Study participants were then given two minutes to write down as many of the words as they could remember. Memory deficit was defined as the recall of four or fewer words.

Analyses were adjusted for education, occupational position, coronary heart disease, stroke, hypertension, use of medication, diabetes, smoking, and alcohol consumption. Results showed that, compared with people with high HDL-C (> 60mg/dL), those with low HDL-C (<40mg/dL) were more likely to have memory deficit at both time points; this association was independent of the presence of the apolipoprotein E e4 (apoE4) allele, a potent risk factor for Alzheimer’s disease.

Table 1. Odds ratio (OR) of memory deficit for people with low HDL-C vs high HDL-C

References

1. Singh-Manoux A, Gimeno D, Kivimaki M, et al. Low HDL cholesterol is a risk factor for deficit and decline in memory in midlife. The Whitehall II study. Arterioscler Thromb Vasc Biol. DOI:10.1161/ATVBAHA.108.163998.

2. Kontush A, Chapman MJ. HDL: Close to our memories? Arterioscler Thromb Vasc Biol. Published online before print June 30, 2008.