Frank Jan de Jong

Atherosclerosis and risk for dementia

Atherosclerosis has been implicated in the development of dementia and its major subtypes, Alzheimers disease and vascular dementia. However, support for this association mainly comes from cross‐sectional studies. We investigated the association of atherosclerosis with dementia and subtypes of dementia during long follow‐up, with various noninvasive measures of atherosclerosis.

Subjective memory complaints, education, and risk of Alzheimer’s disease

Subjective memory complaints are common in the elderly. Although memory complaints are associated with an increased risk of Alzheimers disease in persons with cognitive impairment as well as in persons with normal cognition, they are commonly considered of less importance than objective cognitive measures. We hypothesized that the clinical relevance of subjective memory complaints might vary with educational background.

Thyroid function, the risk of dementia and neuropathologic changes: The Honolulu-Asia Aging Study

Thyroid dysfunction is associated with cognitive impairment and dementia, including Alzheimers disease (AD). It remains unclear whether thyroid dysfunction results from, or contributes to, Alzheimer pathology. We determined whether thyroid function is associated with dementia, specifically AD, and Alzheimer-type neuropathology in a prospective population-based cohort of Japanese-American men. Thyrotropin, total and free thyroxine were available in 665 men aged 71-93 years and dementia-free at baseline (1991), including 143 men who participated in an autopsy sub-study. During a mean follow-up of 4.7 (S.D.: 1.8) years, 106 men developed dementia of whom 74 had AD. Higher total and free thyroxine levels were associated with an increased risk of dementia and AD (age and sex adjusted hazard ratio (95% confidence interval) per S.D. increase in free thyroxine: 1.21 (1.04; 1.40) and 1.31 (1.14; 1.51), respectively). In the autopsied sub-sample, higher total thyroxine was associated with higher number of neocortical neuritic plaques and neurofibrillary tangles. No associations were found for thyrotropin. Our findings suggest that higher thyroxine levels are present with Alzheimer clinical disease and neuropathology.

Unrecognized Myocardial Infarction in Relation to Risk of Dementia and Cerebral Small Vessel Disease

Background and Purpose— Men, but not women, with unrecognized myocardial infarction (MI) have an increased risk of cardiac events and stroke compared with those without MI or with recognized MI. We investigated whether unrecognized MI is also a risk factor for dementia and cerebral small vessel disease (white matter lesions and brain infarction) in 2 population-based cohort studies. Methods— In the Rotterdam Study, 6347 participants were classified at baseline (1990 to 1993) into those with recognized MI (subdivided into Q-wave and non-Q-wave MI), with unrecognized MI, and without MI based on electrocardiography and interview and were followed for incident dementia (n=613) until January 1, 2005. In the Rotterdam Scan Study, 436 nondemented persons were similarly classified based on electrocardiography and interview and underwent brain MRI for the assessment of white matter lesions and brain infarction. Results— In men, unrecognized MI was associated with an increased risk of dementia (compared with men without MI hazard ratio, 2.14; 95% CI, 1.37 to 3.35) and with more white matter lesions and more often brain infarction on MRI. In women, no associations were found with unrecognized MI. Recognized MI was not associated with the risk of dementia in either sex. Men, but not women, with recognized MI had more often any brain infarction or asymptomatic brain infarction, especially if they had Q-wave MI. No consistent associations were found between recognized Q-wave or non-Q-wave MI and severity of white matter lesions. Additional adjustment for cardiovascular risk factors did not change the results. Conclusions— Men with unrecognized MI have an increased risk of dementia and more cerebral small vessel disease.

Organic Anion Transporter 1B1: An Important Factor in Hepatic Thyroid Hormone and Estrogen Transport and Metabolism

Sulfation is an important pathway in the metabolism of thyroid hormone and estrogens. Sulfation of estrogens is reversible by estrogen sulfatase, but sulfation of thyroid hormone accelerates its degradation by the type 1 deiodinase in liver. Organic anion transporters (OATPs) are capable of transporting iodothyronine sulfates such as T4 sulfate (T4S), T3S, and rT3S or estrogen sulfates like estrone sulfate (E1S), but the major hepatic transporter for these conjugates has not been identified. A possible candidate is OATP1B1 because model substrates for this transporter include the bilirubin mimic bromosulfophthalein (BSP) and E1S, and it is highly and specifically expressed in liver. Therefore, OATP1B1-transfected COS1 cells were studied by analysis of BSP, E1S, and iodothyronine sulfate uptake and metabolism. Two Caucasian populations (155 blood donors and 1012 participants of the Rotterdam Scan Study) were genotyped for the OATP1B1-Val174Ala polymorphism and associated with bilirubin, E1S, and T4S levels. OATP1B1-transfected cells strongly induced uptake of BSP, E1S, T4S, T3S, and rT3S compared with mock-transfected cells. Metabolism of iodothyronine sulfates by cotransfected type 1 deiodinase was greatly augmented in the presence of OATP1B1. OATP1B1-Val174 showed a 40% higher induction of transport and metabolism of these substrates than OATP1B1-Ala174. Carriers of the OATP1B1-Ala174 allele had higher serum bilirubin, E1S, and T4S levels. In conclusion, OATP1B1 is an important factor in hepatic transport and metabolism of bilirubin, E1S, and iodothyronine sulfates. OATP1B1-Ala174 displays decreased transport activity and thereby gives rise to higher bilirubin, E1S, and T4S levels in carriers of this polymorphism.

Retinal vessel diameters and the role of inflammation in cerebrovascular disease

Retinal vessels may provide a way to study the cerebral microcirculation. In particular, larger retinal venular diameters have been associated with cerebrovascular disease. An inflammatory response may underlie this association. In a population‐based cohort study among 5,279 participants aged 55 years or older with graded retinal vessel diameters, we observed that greater serum levels of C‐reactive protein and fibrinogen and greater lipoprotein‐associated phospholipase A2 activity were strongly associated with larger venular diameters. Weaker associations were found with arteriolar diameters. Our findings support the hypothesis that larger retinal venular diameters reflect systemic inflammation and suggest that inflammation is involved in cerebrovascular disease. Ann Neurol 2007

Glucocorticoid receptor variant and risk of dementia and white matter lesions

OBJECTIVE Elevated glucocorticoid levels are associated with dementia. A glucocorticoid receptor gene variant (ER22/23EK) is related to relative glucocorticoid resistance. We investigated whether the ER22/23EK allele is associated with dementia and structural brain abnormalities. METHODS This study was performed in two prospective population-based cohort studies among elderly. The first study included 6034 participants who were screened for dementia (mean follow-up 5.8 years). The second study included 1011 elderly subjects with an MRI at baseline and follow-up. The ER22/23EK allele was assessed for association with dementia, cognitive function and white matter lesions. RESULTS The ER22/23EK allele was associated with a decreased risk of dementia. Among non-demented participants, ER22/23EK-carriers had a better performance on psychomotor speed tests than non-carriers. No differences were found in memory function between genotypes. In addition, both presence and progression of white matter lesions was lower in ER22/23EK-carriers. No association was found with brain atrophy on MRI. CONCLUSIONS Our findings suggest a protective effect of the ER22/23EK allele on the risk of dementia and white matter lesions.

Paracetamol (Acetaminophen) in stroke 2 (PAIS 2): Protocol for a randomized, placebo-controlled, double-blind clinical trial to assess the effect of high-dose paracetamol on functional outcome in patients with acute stroke and a body temperature of 36·5°C or above

Rationale In the first hours after stroke onset, subfebrile temperatures and fever have been associated with poor functional outcome. In the first Paracetamol (Acetaminophen) in Stroke trial, a randomized clinical trial of 1400 patients with acute stroke, patients who were treated with high-dose paracetamol showed more improvement on the modified Rankin Scale at three-months than patients treated with placebo, but this difference was not statistically significant. In the 661 patients with a baseline body temperature of 37·0°C or above, treatment with paracetamol increased the odds of functional improvement (odds ratio 1·43; 95% confidence interval: 1·02–1·97). This relation was also found in the patients with a body temperature of 36·5°C or higher (odds ratio 1·31; 95% confidence interval 1·01–1·68). These findings need confirmation. Aim The study aims to assess the effect of high-dose paracetamol in patients with acute stroke and a body temperature of 36·5°C or above on functional outcome. Design The Paracetamol (Acetaminophen) In Stroke 2 trial is a multicenter, randomized, double-blind, placebo-controlled clinical trial. We use a power of 85% to detect a significant difference in the scores on the modified Rankin Scale of the paracetamol group compared with the placebo group at a level of significance of 0·05 and assume a treatment effect of 7%. Fifteen-hundred patients with acute ischemic stroke or intracerebral hemorrhage and a body temperature of 36·5°C or above will be included within 12 h of symptom onset. Patients will be treated with paracetamol in a daily dose of six-grams or matching placebo for three consecutive days. The Paracetamol (Acetaminophen) In Stroke 2 trial has been registered as NTR2365 in The Netherlands Trial Register. Study outcomes The primary outcome will be improvement on the modified Rankin Scale at three-months as analyzed by ordinal logistic regression. Discussion If high-dose paracetamol will be proven effective, a simple, safe, and extremely cheap therapy will be available for many patients with acute stroke worldwide.

Consensus guidelines for lumbar puncture in patients with neurological diseases.

Cerebrospinal fluid collection by lumbar puncture (LP) is performed in the diagnostic workup of several neurological brain diseases. Reluctance to perform the procedure is among others due to a lack of standards and guidelines to minimize the risk of complications, such as post‐LP headache or back pain.

Heterozygosity for the classical galactosemia mutation does not affect ovarian reserve and menopausal age

Female patients with classical galactosemia (galactose-1-phosphate uridyltransferase [GALT] deficiency) frequently suffer from premature ovarian failure, despite treatment with a galactose-restricted diet. Earlier research has suggested an association between heterozygosity for GALT mutations and early menopause. This study evaluates the effect of carriership for classical galactosemia on ovarian reserve and menopausal age. Proven female carriers of classical galactosemia were recruited via the Dutch Galactosemia Society. All 58 participants underwent a structured interview regarding fertility, smoking status, and menopause. To determine ovarian reserve, 42 premenopausal GALT carriers underwent ovarian antral follicle count (AFC) by transvaginal ultrasound and early follicular phase blood sampling for hormonal measurement of follicle-stimulating hormone (FSH), inhibin B, and anti-Müllerian hormone (AMH). These ovarian reserve parameters were compared with a cohort of proven fertile women (n = 166). The mean age at menopause in GALT carriers was 49.7 years, which is not different from the mean age at menopause in the general population in the Netherlands. There was no difference in FSH, inhibin B, and AMH levels or in the AFC (when corrected for age and smoking status) between 42 premenopausal GALT carriers and controls. The authors conclude that there is no evidence that GALT mutation carriership affects ovarian reserve or menopausal age.