Marieke van Oijen

Plasma Aβ1–40 and Aβ1–42 and the risk of dementia: a prospective case-cohort study

Summary Background Amyloid β peptides (Aβ) are important components of plaques in Alzheimers disease. Plasma concentrations of Aβ 1–40 and Aβ 1–42 rise with age and are increased in people with mutations that cause early-onset Alzheimers disease. However, Aβ 1–42 concentrations may decrease early in the dementia process. We postulated that concentrations of Aβ 1–40 and Aβ 1–42 in plasma are associated with risk of dementia. Methods We did a case-cohort study embedded in the prospective, population-based Rotterdam Study. Of 6713 participants at risk for dementia, a random sample of 1756 people was drawn. During follow-up (mean 8·6 years), 392 incident dementia cases were identified. We investigated the association between plasma Aβ concentrations and risk of dementia and its subtypes using Cox proportional hazard models. Findings High concentrations of Aβ 1–40 but not Aβ 1–42 at baseline were associated with an increased risk of dementia. Compared with the first quartile of Aβ 1–40 , age and sex-adjusted hazard ratios for dementia for the second, third, and fourth quartiles were 1·07 (95% CI 0·72–1·58), 1·16 (0·78–1·70), and 1·46 (1·01–2·12). People with an increased Aβ 1–42 /Aβ 1–40 ratio had a reduced risk of dementia. Compared with the first quartile of the Aβ 1–42 /Aβ 1–40 ratio, hazard ratios for the second, third, and fourth quartiles were 0·74 (0·53–1·02), 0·62 (0·44–0·88), and 0·47 (0·33–0·67). Associations were similar for Alzheimers disease and vascular dementia. Interpretation High plasma concentrations of Aβ 1–40 , especially when combined with low concentrations of Aβ 1–42 , indicate an increased risk of dementia. A potential role of plasma Aβ concentrations as a marker of incipient dementia warrants further investigation.

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.

Fibrinogen Is Associated With an Increased Risk of Alzheimer Disease and Vascular Dementia

Background and Purpose— Vascular and inflammatory factors may play an important role in the pathogenesis of dementia. Studies reported an association between plasma levels of inflammation markers and the risk of dementia. Both fibrinogen and C-reactive protein are considered inflammatory markers. Fibrinogen also has important hemostatic properties. We investigated the association of fibrinogen and C-reactive protein with dementia. Methods— The study was based on the prospective population-based Rotterdam Study. Fibrinogen was measured in a random sample of 2835 persons. High-sensitivity C-reactive protein was measured in the total cohort of 6713 persons. We identified 395 incident dementia cases during follow-up (mean, 5.7 years). We estimated the associations of fibrinogen and C-reactive protein with dementia using Cox proportional hazard models. Results— Persons with higher levels of fibrinogen had an increased risk of dementia. The hazard ratio for dementia per SD increase of fibrinogen was 1.26 (95% CI, 1.11 to 1.44), adjusted for age and gender, and 1.30 (95% CI, 1.13 to 1.50) after additional adjustment for cardiovascular factors and stroke. For Alzheimer disease, the adjusted hazard ratio was 1.25 (95% CI, 1.04 to 1.49), and for vascular dementia it was 1.76 (95% CI, 1.34 to 2.30). High levels of C-reactive protein were not associated with an increased risk of dementia. Conclusions— High fibrinogen levels were associated with an increased risk of both Alzheimer disease and vascular dementia, but levels of C-reactive protein were not. This suggests that the increased risk of dementia associated with fibrinogen is because of the hemostatic rather than the inflammatory properties of fibrinogen.

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.

Arterial Stiffness, Cognitive Decline, and Risk of Dementia The Rotterdam Study

Background and Purpose— Arterial stiffness is associated with an increased risk of myocardial infarction and stroke, independent of classical vascular risk factors. Vascular factors and stroke are associated with cognitive function and dementia. We examined whether arterial stiffness was independently associated with cognitive function and dementia. Methods— The present study was based on the Rotterdam Study, a prospective population-based cohort study ongoing since 1990. During the third examination (1997–1999) arterial stiffness was measured by assessment of pulse wave velocity and carotid distensibility. Cognitive function was assessed during the third and fourth examination (2002–2004) with a neuropsychological test battery. We used linear and logistic regression to estimate the association of arterial stiffness with cognitive function and cognitive decline. From the third examination until January 1, 2005, we identified 156 incident dementia cases. Cox proportional hazard models were used to estimate the association between arterial stiffness and the risk of dementia. Results— After adjustment for cardiovascular risk factors we found an association of increased pulse wave velocity with poorer performance on the Stroop test (adjusted &bgr;-coefficient [95% confidence interval] 1.13 [0.26 to 1.99] per standard deviation increase in pulse wave velocity) but not with performance on other cognitive tests. No associations were found between measures of arterial stiffness and cognitive decline or risk of dementia after adjustment for cardiovascular factors. Conclusions— We did not identify arterial stiffness as an independent risk factor of cognitive decline or risk of dementia.

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.

Fasting Insulin Levels and Cognitive Decline in Older Women without Diabetes

Background: Type 2 diabetes has been associated with an increased risk of dementia. To assess possible independent effects of insulin, we investigated the relation of insulin levels to cognitive decline in nondiabetic women. Methods: Fasting plasma insulin levels were measured in mid-life in 1,416 nondiabetic Nurses’ Health Study participants, who also completed cognitive testing that began 10 years later (current age: 70–75 years). Over 4 years, 3 assessments of general cognition, verbal memory, category fluency and attention were administered. Primary outcomes were the Telephone Interview for Cognitive Status (TICS) performance, the global score (average of all tests) and verbal memory (average of verbal recall tests). Linear mixed-effects models were used to calculate the association between insulin and cognitive decline. Results: Higher insulin levels were associated with a faster decline on the TICS and verbal memory. For analysis, batch-specific quartiles of insulin levels were constructed. Compared to the lowest quartile, adjusted differences in the annual rates of decline (with 95% CI values in parentheses) for the second, third and fourth quartiles were: TICS, –0.06 (–0.16, 0.03), –0.14 (–0.24, –0.04), and –0.09 (–0.19, 0.01) points (p trend = 0.04); verbal memory, –0.01 (–0.04, 0.02), –0.05 (–0.08, –0.02), and –0.02 (–0.05, 0.01) units (p trend = 0.02). These associations remained after multivariable adjustment. Conclusions: Our study provides evidence for a potential role of higher fasting insulin levels in cognitive decline, possibly independent of diabetes.

Lipoprotein-associated phospholipase A2 is associated with risk of dementia.

High levels of the inflammatory marker lipoprotein‐associated phospholipase A2 (Lp‐PLA2) have been proposed to be a predictor of coronary heart disease and stroke. Because both inflammation and vascular disease are associated with dementia, the objective of the present study was to examine the association between Lp‐PLA2 and the risk of dementia.

Nodding syndrome—a new hypothesis and new direction for research

Nodding syndrome (NS) is an unexplained neurological illness that mainly affects children aged between 5 and 15 years. NS has so far been reported from South Sudan, northern Uganda, and Tanzania, but in spite of extensive investigations, the aetiology remains unknown. We hypothesize that blackflies (Diptera: Simuliidae) infected with Onchocerca volvulus microfilariae may also transmit another pathogen. This may be a novel neurotropic virus or an endosymbiont of the microfilariae, which causes not only NS, but also epilepsy without nodding. This hypothesis addresses many of the questions about NS that researchers have previously been unable to answer. An argument in favour of the hypothesis is the fact that in Uganda, the number of new NS cases decreased (with no new cases reported since 2013) after ivermectin coverage was increased and with the implementation of a programme of aerial spraying and larviciding of the large rivers where blackflies were breeding. If confirmed, our hypothesis will enable new strategies to control NS outbreaks.

Prevalence of polyneuropathy in the general middle-aged and elderly population

Objective: To determine the prevalence of chronic polyneuropathy in an unselected community-dwelling population of middle-aged and elderly people. Methods: The current study was embedded in the prospective, population-based Rotterdam Study. Between June 2013 and October 2015, 1,310 participants (mean age 70 years, 55% female) were screened for the presence of polyneuropathy. This screening consisted of a questionnaire, neurologic examination, and nerve conduction studies. Polyneuropathy was diagnosed by a consensus panel that categorized participants into no, possible, probable, or definite polyneuropathy, depending on the level of abnormality of the screening. Medical records were scrutinized to evaluate whether the disorder was diagnosed before and laboratory investigations were performed to determine the presence of associated risk factors. Results: Prevalence of definite polyneuropathy was 5.5% (95% confidence interval 4.4–6.9), age-standardized to the population of the Netherlands 4.0% (3.1–5.3). Prevalence was higher in male participants (6.7% compared to 4.5%) and increased with age. When combining probable and definite polyneuropathy, age-standardized prevalence was 9.4% (7.9–11.1). Almost half of the polyneuropathies (49%) were newly diagnosed. The majority of polyneuropathies were idiopathic (46%). Diabetes, present in 31% of participants with polyneuropathy, was the most commonly found risk factor. Conclusions: Prevalence of polyneuropathy in the general middle-aged and elderly population is at least 4%, and increases with age. Almost half of the cases were newly diagnosed, indicating that the presence of polyneuropathy is underreported or underdiagnosed. Currently, almost half of the polyneuropathies are idiopathic. Future prospective cohort studies should focus on identifying new determinants of polyneuropathy.