Diagnostic value of symptoms in chronic polyneuropathy: The Erasmus Polyneuropathy Symptom Score.

In this study, we evaluated the diagnostic value of symptoms of chronic polyneuropathy and to construct and validate a simple questionnaire that can help diagnose chronic polyneuropathy. In a multi-step procedure, we initially compiled a 12-item questionnaire concerning polyneuropathy symptoms. The questionnaire was completed by 117 polyneuropathy patients and 188 controls (headache, transient ischemic attack, multiple sclerosis). First, we calculated sensitivity, specificity and likelihood ratios of each symptom. Next, we used multi-variable logistic regression to create a model that could discriminate patients from controls, using only the most informative symptoms and their frequency of occurrence. Based on the regression coefficients, we developed a simple scoring system (Erasmus Polyneuropathy Symptom Score, E-PSS), which was externally validated in 140 cases with chronic idiopathic axonal polyneuropathy and 96 controls without polyneuropathy. We assessed performance with discrimination (area under the curve, AUC) and calibration analyses. Numb and tingling feet were most frequently reported by polyneuropathy patients and had the highest sensitivity. Walking on cotton wool and allodynia had the highest specificity. Logistic regression yielded a model that contained these four symptoms, complemented with balance problems and tingling hands. Based on this analysis, the E-PSS was created, ranging from 0 to 14. The E-PSS had a good performance (AUC = 0.92) in the derivation set and proved to be valid in the external population (AUC = 0.95). In conclusion, the Erasmus Polyneuropathy Symptom Score (E-PSS) is a simple, validated six-item score that takes the presence and frequency of six different symptoms into account and it may be a helpful tool to screen individuals for the presence of chronic polyneuropathy.

The epidemiology and risk factors of chronic polyneuropathy.

Polyneuropathy is a disabling condition of the peripheral nerves, characterized by symmetrical distal numbness and paresthesia, often accompanied with pain and weakness. Although the disease is often encountered in neurological clinics and is well known by physicians, incidence and prevalence rates are not well known. We searched EMBASE, Medline, Web-of-science, Cochrane, PubMed Publisher, and Google Scholar, for population-based studies investigating the prevalence of polyneuropathy and its risk factors. Out of 5119 papers, we identified 29 eligible studies, consisting of 11 door-to-door survey studies, 7 case-control studies and 11 cohort/database studies. Prevalence of polyneuropathy across these studies varies substantially. This can partly be explained by differences in assessment protocols and study populations. The overall prevalence of polyneuropathy in the general population seems around 1% and rises to up to 7% in the elderly. Polyneuropathy seemed more common in Western countries than in developing countries and there are indications that females are more often affected than males. Risk factor profiles differ across countries. In developing countries communicable diseases, like leprosy, are more common causes of neuropathy, whereas in Western countries especially diabetes, alcohol overconsumption, cytostatic drugs and cardiovascular disease are more commonly associated with polyneuropathy. In all studies a substantial proportion of polyneuropathy cases (20-30%) remains idiopathic. Most of these studies have been performed over 15 years ago. More recent evidence suggests that the prevalence of polyneuropathy in the general population has increased over the years. Future research is necessary to confirm this increase in prevalence and to identify new and potentially modifiable risk factors.

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.

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 beta-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.

Subjective memory complaints, education, and risk of Alzheimer's disease.

BACKGROUND: Subjective memory complaints are common in the elderly. Although memory complaints are associated with an increased risk of Alzheimer's 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. METHODS: The study was performed within the Rotterdam Study, a prospective population-based cohort study among 7983 persons 55 years and older. Subjective memory complaints and level of education were assessed in the baseline interview (1990 to 1993). During a mean follow-up of 9.0 years we identified 568 incident Alzheimer's disease patients. We estimated the association between subjective memory complaints and risk of dementia by means of Cox proportional hazard models. RESULTS: The association between subjective memory complaints and risk of Alzheimer's disease varied across levels of education. The risk of Alzheimer's disease associated with subjective memory complaints was higher in highly educated persons (age- and sex-adjusted hazard ratio, 2.33; 95% confidence interval [CI], 1.00-5.49) than in persons with a low education (age- and sex-adjusted hazard ratio, 1.53; 95% CI, 1.15-2.05) (P value for interaction, .02). In highly educated persons without objective cognitive impairment (Mini-Mental State Examination score, 29 or 30) the risk of Alzheimer's disease was highest (age- and sex-adjusted hazard ratio, 2.98; 95% CI, 1.76-5.02). CONCLUSIONS: Especially in persons with a high level of education who still perform well on formal cognitive tests, subjective memory complaints might be an important first sign of imminent Alzheimer's disease.

Ivermectin Treatment in Patients With Onchocerciasis-Associated Epilepsy: Protocol of a Randomized Clinical Trial.

BACKGROUND: Many studies have reported an association between epilepsy, nodding syndrome (NS), and onchocerciasis (river blindness). A high prevalence of epilepsy has been noted particularly in onchocerciasis hyperendemic areas where onchocerciasis is not or insufficiently controlled with mass ivermectin distribution. There is evidence that increasing the coverage of ivermectin reduces the incidence of epilepsy, and anecdotal evidence suggests a reduction in seizure frequency in onchocerciasis-associated epilepsy (OAE) patients who receive ivermectin. Finding an alternative treatment for epilepsy in these patients will have major consequences. OBJECTIVE: The goal of the study is to assess whether ivermectin treatment decreases the frequency of seizures and leads to seizure freedom in OAE patients, including patients with NS. If we are able to demonstrate such an effect, this would strengthen the argument that onchocerciasis is causing epilepsy and therefore we should increase our efforts to eliminate onchocerciasis. METHODS: We will conduct a randomized clinical trial in the Democratic Republic of Congo to compare seizure freedom in onchocerciasis-infested epilepsy patients who receive immediate ivermectin treatment with delayed (after 4 months) ivermectin treatment. All participants will simultaneously receive antiepilepsy drugs (AEDs) according to local guidelines for epilepsy treatment. The primary endpoint is seizure freedom defined as no seizures during the 4 month of follow-up. Secondary endpoint is significant (>50%) seizure reduction compared to baseline seizure frequency. Reduction of seizures will be compared between ivermectin and nonivermectin arms. RESULTS: Start of enrollment is planned for August 2017, and we expect to have enrolled all 110 participants by December 2017. Results are expected in June 2018. CONCLUSIONS: If ivermectin treatment in addition to AEDs is able to lead to seizure freedom or significantly reduces seizure frequency in OAE patients, this will have major consequences for epilepsy treatment in onchocerciasis-endemic regions. Ivermectin is donated for free and in non Loa-Loa-endemic regions has negligible side effects. Reducing the burden of epilepsy will have a major impact on quality of life and socioeconomic status of families with affected members in Africa. TRIAL REGISTRATION: ClinicalTrials.gov NCT03052998; https://clinicaltrials.gov/ct2/show/NCT03052998 (Archived by WebCite at http://www.webcitation.org/6roFVQSG0).

Onchocerciasis-associated epilepsy: From recent epidemiological and clinical findings to policy implications.

A high prevalence of epilepsy is reported in many onchocerciasis-endemic regions. In this paper we discuss recent epidemiological and clinical aspects as well as public health implications of onchocerciasis-associated epilepsy (OAE) and propose a strategy to reduce the burden of disease. OAE probably presents in a variety of clinical manifestations, including the nodding syndrome and the Nakalanga syndrome. The most common clinical presentation, however, is generalized (primarily tonic-clonic) seizures. A characteristic of OAE is the onset of seizures between the ages of 3 and 18 years and clustering in certain families and villages close to rapid-flowing black-fly-infested rivers. A strategy combining active surveillance for epilepsy with early treatment with antiepileptic drugs and prevention of onchocerciasis by increasing the geographical and therapeutic coverage of community-directed treatment with ivermectin (CDTi) may considerably decrease the burden of disease.

Plasma Abeta(1-40) and Abeta(1-42) and the risk of dementia: a prospective case-cohort study.

BACKGROUND: Amyloid beta peptides (Abeta) are important components of plaques in Alzheimer's disease. Plasma concentrations of Abeta(1-40) and Abeta(1-42) rise with age and are increased in people with mutations that cause early-onset Alzheimer's disease. However, Abeta(1-42) concentrations may decrease early in the dementia process. We postulated that concentrations of Abeta(1-40) and Abeta(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 Abeta concentrations and risk of dementia and its subtypes using Cox proportional hazard models. FINDINGS: High concentrations of Abeta(1-40) but not Abeta(1-42) at baseline were associated with an increased risk of dementia. Compared with the first quartile of Abeta(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 Abeta(1-42)/Abeta(1-40) ratio had a reduced risk of dementia. Compared with the first quartile of the Abeta(1-42)/Abeta(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 Alzheimer's disease and vascular dementia. INTERPRETATION: High plasma concentrations of Abeta(1-40), especially when combined with low concentrations of Abeta(1-42), indicate an increased risk of dementia. A potential role of plasma Abeta concentrations as a marker of incipient dementia warrants further investigation.

Polymorphisms in the interleukin 6 and transforming growth factor beta1 gene and risk of dementia. The Rotterdam Study.

Inflammatory mechanisms are involved in the pathogenesis of dementia. Inflammatory cytokines, including interleukin-6 (IL-6) and transforming growth factor beta1 (TGFbeta1), have been found in association with Alzheimer pathology and there is evidence for direct involvement of these cytokines in formation of amyloid plaques. Polymorphisms in genes encoding for IL-6 and TGFbeta1 are associated with plasma levels of IL-6 and TGFbeta1. Studies examining the association between polymorphisms in these genes and dementia yielded conflicting results. The purpose of this study was to examine the association between genetic variance in IL-6 and TGFbeta1 and risk of dementia. We examined this association in the Rotterdam Study, a prospective population-based cohort study in the elderly. Polymorphisms in the IL-6 (-174G>C) and TGFbeta1 gene (-800G>A, -509C>T, +10T>C, +25G>C and 263C>T) were genotyped and haplotypes of the TGFbeta1 gene were constructed. In a random subset IL-6 plasma levels were measured. During follow-up (mean 9.2 years), 743 dementia cases were identified. We estimated the association between individual polymorphisms and haplotypes with dementia with Cox' proportional hazard models. No association was found between the -174G>C polymorphism in the IL-6 gene and risk of dementia. No association was found between polymorphisms and constructed haplotypes in the TGFbeta1 gene and risk of dementia or Alzheimer's disease. No association was found between IL-6 genotype and IL-6 plasma levels in the random subset. Associations did not differ across APOE genotypes. Our findings do not suggest involvement of genetic variance in IL-6 and TGFbeta1 in the development of dementia.

Resective epilepsy surgery in childhood: the Dutch experience 1992-2002.

PURPOSE: We present the outcome of resective epilepsy surgery in 69 pediatric patients who participated in the Dutch Collaborative Epilepsy Surgery Program (DCESP) between 1992 and 2002 with special emphasis on long-term follow-up. METHODS: Sixty-nine children (aged 3 months to 17 years) operated on before 2003 were included in this study (34 temporal resections (49%), 17 extra-temporal resections (24%) and 19 hemispherectomies (27%)). Engel classification was used to assess seizure outcome annually. Cognitive outcome was assessed if possible. Two telephone surveys were carried out with an interval of 2(1/2) years to obtain data on seizure frequency, use of AEDs and on aspects op psychosocial development. Kaplan-Meier survival curves were constructed to assess recurrence of seizures after initial postsurgical seizure freedom, based on both telephone surveys. RESULTS: Seventy percent scored Engel 1, 18% Engel 2, 6% Engel 3 and 6% Engel 4 at the time of the first telephone survey (2(1/2) years later: 77% Engel 1, 8% Engel 2, 12% Engel 3 and 3% Engel 4). Temporal resections were associated with the best seizure outcome (Engel 1 74% and 82%). AEDs could be withdrawn successfully in 53% of patients at time of the last follow-up. No negative impact on cognition was found. The first long-term follow-up (mean 4.5 years after surgery) measurement showed recurrence of seizures after initial seizure freedom in 17%. At time of the second long-term follow-up measurement (mean 7.5 years after surgery) this percentage had increased to 21%. CONCLUSIONS: Our results support previous reports that surgery for intractable epilepsy in pediatric patients can be safely performed with satisfactory long-term results. Best results are attained in temporal resections.

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.

Nodding syndrome and epilepsy in onchocerciasis endemic regions: comparing preliminary observations from South Sudan and the Democratic Republic of the Congo with data from Uganda.

BACKGROUND: Nodding syndrome (NS) is an epilepsy disorder occurring in children in South Sudan, northern Uganda and Tanzania. The etiology of NS is unknown, but epidemiological studies demonstrate an association between NS and onchocerciasis. METHODS: Between November 2013 and July 2015 we visited onchocerciasis endemic regions in South Sudan, Uganda, and the Democratic Republic of the Congo (DRC) to assess the epilepsy situation. In South Sudan we interviewed patients and affected families, health officials, colleagues and healthcare workers, and performed a small household survey to estimate the epilepsy prevalence in the village of Mvolo, Western Equatoria State. Most information from Uganda was collected through discussions with colleagues and a review of published literature and reports. In the Bas-Uélé district of the DRC, we visited the villages of Liguga, Titule and Dingila, interviewed patients with epilepsy and family members and conducted a preliminary entomological assessment. RESULTS: In South Sudan there is an ongoing NS and epilepsy epidemic in the Western Equatoria state that started around 1990. A survey of 22 households in Mvolo revealed that 28 out of 168 (16.7%) children suffered from NS or another form of epilepsy. Thirteen (59%) households had at least one child, and nine (41%) households at least two children with NS or another form of epilepsy. In northern Uganda, an NS and epilepsy epidemic started around 2000. The occurrence of new NS cases has been in decline since 2008 and no new NS cases were officially reported in 2013. The decline in NS cases coincided with the bi-annual distribution of ivermectin and the treatment of blackfly-breeding rivers with larvicides. In Bas-Uélé district in the DRC, epilepsy appears to be endemic with cases clustered in villages close to blackfly-infested, rapid-flowing rivers. The majority of epilepsy cases in Liguga, Dingila and Titule presented with generalized (tonic-clonic) seizures without nodding, but with mental retardation. In Titule, an epilepsy prevalence of 2.3% was documented. The only anthropophilic species of blackfly collected in the region belonged to the Simulium damnosum complex. CONCLUSION: Blackflies may play a key role in the transmission of an etiological agent that either directly or indirectly cause, not only NS, but also other forms of epilepsy in onchocerciasis endemic regions.

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.

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.

Shorter telomeres may mark early risk of dementia: preliminary analysis of 62 participants from the nurses' health study.

BACKGROUND: Dementia takes decades to develop, and effective prevention will likely require early intervention. Thus, it is critical to identify biomarkers of preclinical disease, allowing targeting of high-risk subjects for preventive efforts. Since telomeres shorten with age and oxidative stress, both of which are important contributors to the onset of dementia, telomere length might be a valuable biomarker. METHODOLOGY/PRINCIPAL FINDINGS: Among 62 participants of the Nurses' Health Study, we conducted neurologic evaluations, including patient and caregiver interviews, physical exam, neurologic exam, and neuropsychologic testing. We also conducted magnetic resonance imaging (MRI) in a sample of 29 of these women. In these preliminary data, after adjustment for numerous health and lifestyle factors, we found that truncated telomeres in peripheral blood leukocytes segregate with preclinical dementia states, including mild cognitive impairment (MCI); the odds of MCI were 12-fold higher (odds ratio = 12.00, 95% confidence interval 1.24-116.5) for those with shorter telomere length compared to longer telomere length. In addition, decreasing telomere length was strongly related to decreasing hippocampal volume (p = 0.038). CONCLUSIONS: These preliminary data suggest that telomere length may be a possible early marker of dementia risk, and merits further study in large, prospective investigations.

Atherosclerosis and risk for dementia.

OBJECTIVE: Atherosclerosis has been implicated in the development of dementia and its major subtypes, Alzheimer's 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. METHODS: This study was based on 6,647 participants in the Rotterdam Study, a population-based prospective cohort study among 7,983 elderly subjects. At baseline (1990-1993) and at the third survey (1997-1999), common carotid intima media thickness, carotid plaques, and peripheral arterial disease (measured as ankle-brachial index) were measured. During follow-up (mean, 9.0 years), 678 subjects developed dementia. We estimated the associations of different measures of atherosclerosis with risk for dementia and subtypes of dementia by means of Cox proportional hazard models. Analyses were repeated and stratified on duration of follow-up. To evaluate competing risk for mortality, we examined the association between measures of atherosclerosis and risk for dementia or mortality by combining the two in a single outcome measure. RESULTS: We found that atherosclerosis, predominantly carotid atherosclerosis, was associated with an increased risk for dementia during short follow-up. This association attenuated with longer follow-up, likely because of the strong association between atherosclerosis and mortality. The associations did not differ across apolipoprotein E genotypes. INTERPRETATION: Our findings suggest that atherosclerosis is associated with an increased risk for dementia. Stronger associations between atherosclerosis and mortality may attenuate the association between atherosclerosis and dementia in prospective cohort studies with long follow-up periods.

Polymorphisms and haplotypes in the C-reactive protein gene and risk of dementia.

OBJECTIVE: Inflammation plays a role in the pathogenesis of dementia and Alzheimer's disease (AD). Studies examining serum levels of C-reactive protein in relation to dementia yielded conflicting results. Since serum levels of C-reactive protein are partly determined by genetic factors, we examined the association between genetic variation in the C-reactive protein gene with dementia and AD. METHODS: This study was performed in the Rotterdam Study, a population-based prospective cohort study among elderly. Polymorphisms in the C-reactive protein gene (1184C>T, 2042C>T and 2911C>G) tagging the common haplotypes were genotyped and haplotypes were constructed. During follow-up (mean 9.2 years) 607 dementia cases were identified. We estimated the association between polymorphisms and haplotypes with dementia and AD with Cox' proportional hazard models. RESULTS: The T allele of the C-reactive protein 2042C>T polymorphism, related to lower serum levels of C-reactive protein, was associated with a lower risk of dementia and AD. This association was strongest in APOE epsilon4 allele carriers. CONCLUSION: These findings suggest that C-reactive protein plays a role in development of dementia.

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

OBJECTIVE: 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. METHODS: Within the Rotterdam Study, a population-based prospective cohort study, we performed a case-cohort study. Of the 6,713 participants at risk for dementia, a random sample of 1,742 individuals was drawn. During follow-up (mean, 5.7 years), 302 incident dementia cases were identified. Cox proportional hazard models were used to estimate the association of Lp-PLA2 and dementia. RESULTS: We found that subjects with higher levels of Lp-PLA2 had an increased risk of dementia. Compared with the first quartile of Lp-PLA2, age- and sex-adjusted hazard ratios (HRs; 95% confidence interval [CI]) for dementia for the second, third, and fourth quartiles were 1.19 (0.78-1.81), 1.15 (0.74-1.79), and 1.56 (1.03-2.37), respectively (p value for trend 0.04). Additional adjustment for cardiovascular and inflammatory factors did not change the estimates. INTERPRETATION: This is the first study to our knowledge that shows that Lp-PLA2 is associated with the risk of dementia independent of cardiovascular and inflammatory factors and provides evidence for a potential role of Lp-PLA2 in identifying subjects at risk for dementia.