NT-proBNP and changes in cognition and global brain structure: The Rotterdam Study

Objective

To investigate the association between N-terminal pro-B-type natriuretic peptide (NT-proBNP) and changes in cognition and global brain structure.

Methods

In the Rotterdam Study, baseline NT-proBNP was assessed at baseline from 1997 to 2008. Between 1997 and 2016, participants without dementia or stroke at baseline (n = 9566) had repeated cognitive tests (every 3–6 years) for global cognitive function, executive cognitive function, fine manual dexterity, and memory. Magnetic resonance imaging of the brain was performed repeatedly at re-examination visits between 2005 and 2015 for 2607 participants to obtain brain volumes, focal brain lesions, and white matter microstructural integrity as measures of brain structure.

Results

Among 9566 participants (mean age 65.1 ± 9.8 years), 5444 (56.9%) were women, and repeated measures of cognition were performed during a median follow-up time of 5.5 (range 1.1–17.9) years, of whom 2607 participants completed at least one brain imaging scan. Higher levels of NT-proBNP were associated with a faster decline of scores in the global cognitive function (p value = 0.003) and the Word-Fluency test (p value = 0.003) but were not related to a steeper deterioration in brain volumes, global fractional anisotropy, and mean diffusivity, as indicators of white matter microstructural integrity, or focal brain lesions.

Conclusions

Higher baseline NT-proBNP levels were associated with a faster decline in cognition; however, no association with global brain structure was found.     

Cerebral white matter lesions and cognitive function: the Rotterdam Scan Study

Cerebral white matter lesions (WMLs) have been associated with cognitive dysfunction. Whether periventricular or subcortical WMLs relate differently to cognitive function is still uncertain. In addition, it is unclear whether WMLs are related to specific cognitive domains such as memory or psychomotor speed. We examined the relationship between periventricular and subcortical WMLs and cognitive functioning in 1,077 elderly subjects randomly sampled from the general population. Quantification of WMLs was assessed by means of an extensive rating scale on 1.5-T magnetic resonance imaging scans. Cognitive function was assessed by using multiple neuropsychological tests from which we constructed compound scores for psychomotor speed, memory performance, and global cognitive function. When analyzed separately, both periventricular and subcortical WMLs were related to all neuropsychological measures. When periventricular WMLs were analyzed conditional on subcortical WMLs and vice versa, the relationship between periventricular WMLs and global cognitive function remained unaltered whereas the relationship with subcortical WMLs disappeared. Subjects with most severe periventricular WMLs performed nearly 1 SD below average on tasks involving psychomotor speed, and more than 0.5 SD below average for global cognitive function. Tasks that involve speed of cognitive processes appear to be more affected by WMLs than memory tasks.     

Executive dysfunction in vascular cognitive impairment in the consortium to investigate vascular impairment of cognition study

Background and purposeThe importance of executive dysfunction is increasingly recognized in the dementia syndrome. Although executive dysfunction has been associated with subcortical ischemic lesions, it may not be unique to VCI or to its clinical subtypes.MethodsSecondary analysis of the CIVIC study, a multi-centre memory clinic cohort study. An executive dysfunction index variable was created using 30 items from the clinical evaluation.ResultsOf 1347 patients, 151 had a baseline diagnosis of no cognitive impairment (NCI), 463 had AD, 324 had VCI, 97 had vascular cognitive impairment not dementia (VCI-ND) and 253 had non-vascular CIND. Those with VCI and AD had higher mean executive dysfunction index values than those with NCI (F = 160.2, p < 0.01). Within the VCI subtypes, people with VaD and mixed dementia had the highest mean executive dysfunction index values (F = 92.5, p < 0.01). Higher executive dysfunction index values were significantly correlated with lower MMSE scores (R = 0.70, p < 0.01), higher Functional Rating Scale scores (R = 0.77, p < 0.01) and higher Geriatric Depression Score values (R = 0.11, p < 0.01). Compared to those who had a lower burden of executive dysfunction, patients with more executive dysfunction (index values > = 0.2) were more likely to be institutionalized (HR = 5.2, p < 0.01) or to die (HR = 2.4, p < 0.01) during the next 30 months.ConclusionsExecutive dysfunction is common in both AD and VCI. It is associated with poor performance on other measures of cognition and function. The presence of executive dysfunction is associated with worse near-term outcomes.     

The relation between white-matter lesions and cognition

PURPOSE OF REVIEW: To summarize recent findings and developments in the field of the relation between white-matter lesions and cognition. RECENT FINDINGS: Recent studies have provided further evidence that white-matter lesions exert a detrimental effect on cognitive profile. New magnetic-resonance techniques may help in clarifying the meaning and extent of this effect. Evidence is also increasing about lesion progression occurring over time, at least in patients with severe white-matter lesions, and this progression is one of the factors related to cognitive decline in the elderly. The need to delay or halt the progression of white-matter lesions has led to clarification of the role of some risk factors and to performance of therapeutic trials where white-matter lesions are used as a surrogate marker for the end point of small-vessel disease. In addition to cognitive effects, white-matter lesions have a role in the decline of other functional performances, and this places individuals with higher-grade lesions at increased risk of developing disability. SUMMARY: White-matter lesions cannot be considered as mere incidental findings, at least in patients who show severe lesions. The pathogenesis of white-matter lesions must be clarified further and strategies found to delay their progression.     

Homocysteine, silent brain infarcts, and white matter lesions: The Rotterdam Scan Study

Silent brain infarcts and white matter lesions are frequently seen on magnetic resonance imaging in healthy elderly people and both are associated with an increased risk of stroke and dementia. Plasma total homocysteine may be a potentially modifiable risk factor for stroke and dementia. We examined whether elevated total homocysteine levels are associated with silent brain infarcts and white matter lesions. The Rotterdam Scan Study is a population-based study of 1,077 people aged 60 to 90 years who had cerebral magnetic resonance imaging. The cross-sectional relation of total homocysteine with silent infarcts and white matter lesions was analyzed with adjustment for cardiovascular risk factors. The mean plasma total homocysteine level was 11.5 micromol/l (standard deviation 4.1). The risk of silent brain infarcts increased with increasing total homocysteine levels (odds ratio 1.24/standard deviation increase, 95% confidence interval 1.06-1.45). The severity of periventricular white matter lesions and extent of subcortical white matter lesions were also significantly associated with total homocysteine levels, even after excluding those with silent brain infarcts. The overall risk of having either a silent brain infarct or severe white matter lesions was strongly associated with total homocysteine levels (odds ratio 1.35/standard deviation increase, 95% confidence interval 1.16-1.58). We concluded that total homocysteine levels are associated with silent brain infarcts and white matter lesions independent of each other and of other cardiovascular risk factors.     

Rates of decline distinguish Alzheimer's disease and mild cognitive impairment relative to normal aging: integrating cognition and brain function

AIMS: Increasing age is the strongest risk factor for Alzheimer's disease (AD). Yet, departure from normal age-related decline for established markers of AD including memory, cognitive decline and brain function deficits, has not been quantified. METHODS: We examined the cross-sectional estimates of the "rate of decline" in cognitive performance and psychophysiological measures of brain function over age in AD, preclinical (subjective memory complaint-SMC, Mild Cognitive Impairment-MCI) and healthy groups. Correlations between memory performance and indices of brain function were also conducted. RESULTS: The rate of cognitive decline increased between groups: AD showed advanced decline, and SMC/MCI groups represented intermediate stages of decline relative to normal aging expectations. In AD, advanced EEG alterations (excessive slow-wave/reduced fast-wave EEG, decreased working memory P450 component) were observed over age, which were coupled with memory decline. By contrast, MCI group showed less severe cognitive changes but specific decreases in the working memory N300 component and slow-wave (delta) EEG, associated with decline in memory. DISCUSSION AND INTEGRATIVE SIGNIFICANCE: While the cognitive data suggests a continuum of deterioration associated with increasing symptom severity across groups, integration with brain function measures points to possible distinct compensatory strategies in MCI and AD groups. An integrative approach offers the potential for objective markers of the critical turning point, with age as a potential factor, from mild memory problems to disease.     

The association of serum immunoglobulins with cognition and dementia: the Rotterdam Study

Journal of Neurology - Chronic inflammation is involved in the pathophysiology of dementia, but the association of serum immunoglobulins with dementia has been understudied and longitudinal data...     

The 5 alpha-reductase in the brain: molecular aspects and relation to brain function.

All the classes of hormonal steroids physiologically produced in the body (androgens, estrogens, progestagens, and corticosteroids) are able to exert important effects on the brain, but the mechanisms of their actions are not always well understood. Steroids may interact with intracellular receptors to activate the genome, but some of their effects are probably extragenomic and involve interactions with cellular membranes. Moreover, not all the steroids act always in their native molecular form; a large group of them must actually be transformed into "active" metabolites. This may occur at the level of their respective target structures. For example, androgens are metabolized in the brain into estrogens and into 5 alpha-reduced androgens, like 5 alpha-androstan-17 beta-ol-3-one (dihydrotestosterone; DHT) and 5 alpha-androstan-3 alpha, 17 beta-diol (3 alpha-diol). Progesterone, and possibly corticosteroids, may also be transformed into their corresponding 5 alpha-reduced metabolites. Also the cellular target (neurons and/or glial cells) of the hormonal steroids in the brain is not always clear. This review analyzes in detail one of the two major enzymatic systems that transform steroids in the brain, namely the 5 alpha-reductase-3 alpha-(3 beta)-hydroxysteroid dehydrogenase pathway. An active 5 alpha-reductase-3 alpha-hydroxysteroid dehydrogenase system is widely distributed in practically all CNS structures in all phases of development. In the brain, this enzymatic system is not regulated by castration or sex steroid administration; furthermore, neural inputs seem to be ineffective at the hypothalamic level. A recent interesting finding is the presence of high concentrations of the 5 alpha-reductase in the white matter. This probably is due to the fact that the white matter is particularly rich in myelin membranes, with which the enzymatic activity appears to be associated. An active 5 alpha-reductase activity has also been shown to be present in peripheral myelinated nerves. The localization in myelin membranes may suggest a possible involvement of 5 alpha-reduced metabolites of the different steroids in the process of myelination. The presence of the 5 alpha-reductase was analyzed in neurons, astrocytes, and oligodendrocytes isolated from the brains of male rats, as well as in neurons and glial cells grown in culture. Neurons appear to be more active than glial cells in converting testosterone into DHT. Only neurons possess aromatase activity.(ABSTRACT TRUNCATED AT 400 WORDS)     

Homocysteine and cognitive function in the elderly: the Rotterdam Scan Study

BACKGROUND: Elevated plasma total homocysteine (tHcy) concentrations are associated with AD and vascular dementia, but the relation with cognitive performance in nondemented elderly people is not known. OBJECTIVE: To examine the association of tHcy and cognitive function in the elderly, and assess whether this may be mediated by structural brain changes on MRI. METHODS: The Rotterdam Scan Study is a population-based study of 1,077 nondemented elderly. Cognitive performance was assessed, and compound scores were constructed for psychomotor speed, memory function, and global cognitive function. Cerebral infarcts, white matter lesions, and generalized brain atrophy were measured on MRI. The cross-sectional relationship between tHcy levels and neuropsychological test scores was assessed by multiple regression. RESULTS: Mean tHcy level was 11.5 micro mol/L (SD 4.1). Increasing tHcy levels were associated with lower scores for psychomotor speed, memory function, and global cognitive function, and this was largely due to the association with tHcy levels in the upper quintile (>14 micro mol/L). Adjusted differences between test scores of participants in the upper quintile as compared with the lower four quintiles of tHcy were -0.26 (95% CI: -0.37; -0.14) for psychomotor speed, -0.13 (95% CI: -0.27; 0.01) for memory function, and -0.20 (95% CI: -0.30; -0.11) for global cognitive function. These associations were not mediated by structural brain changes on MRI. CONCLUSION: Elevated tHcy levels are associated with decreased cognitive performance in nondemented elderly people, and the relation was most marked for psychomotor speed. This association was independent of structural brain changes on MRI.     

Impact of regional white matter lesions on cognitive function in subcortical vascular cognitive impairment

Abstract

Objectives:

Exact characterization and localization of white matter lesions (WMLs) as they relate and contribute to vascular cognitive impairment is highly debated. The purpose of this study was to investigate the impact of WML on cognitive function by using a new anatomy-based classification method.

Methods:

We detected WML accurately by using a three-dimensional fluid-attenuated inversion recovery (3D FLAIR) imaging technique and subsequently segmented WMLs by using an anatomy-based method. Participants included 56 consecutive patients diagnosed with subcortical vascular cognitive impairment (SubVCI). The volume of WMLs in different anatomic regions was measured. The volume of the hippocampus, the corpus callosum (CC), any lacunar infarcts, total gray matter (GM), and total brain volumes were also calculated.

Results:

Hippocampal (P = 0·005) as well as temporal WML volumes (P = 0·039) were both independently associated with mini-mental state examination (MMSE) score. Only the parietal WML volume (P = 0·000) was independently associated with Montreal Cognitive Assessment (MoCA) score. Frontal WMLs were independently correlated with executive function. Occipital WMLs were independently associated with visuospatial and recall function. Language impairment was independently correlated with both parietal GM and parietal WML volume. Functions related to orientation were independently associated with parietal WML volume.

Discussion:

The volume of WMLs in the temporal region as well as in the hippocampus were both independently associated with MMSE score. For the MoCA score, however, only parietal WML volumes were independently correlated. White matter lesions within different anatomic regions were separately correlated with different subdomains of cognitive function.     

Cerebral white matter lesions and subjective cognitive dysfunction: the Rotterdam Scan Study

OBJECTIVE: To determine the relationship between cerebral white matter lesions (WML) and subjective cognitive dysfunction. BACKGROUND: Subjective cognitive dysfunction is present when a person perceives failures of cognitive function. When annoying enough, these failures will be expressed as complaints. Subjective cognitive dysfunction may be a prelude to or coincide with objective cognitive impairment. WML have been related to objective cognitive impairment and dementia, but their relationship with subjective cognitive dysfunction is not clear. Previous population-based studies on the latter relationship have been limited in sample size, recording of subjective cognitive function, and assessment of WML severity. METHODS: We randomly sampled 1,049 elderly nondemented participants from the general population. Data on subjective cognitive dysfunction and its progression were derived from a 15-item questionnaire. Objective cognitive performance was assessed using a series of neuropsychological tests. WML were scored on MRI for periventricular and subcortical regions separately. RESULTS: WML were associated with more subjective cognitive failures. WML were more severe for participants reporting progression of these failures compared with participants without these failures, especially within participants with better than average cognitive performance (p = 0.008, for periventricular WML). Participants with severe WML reported progression of cognitive failures more than twice as often than did those with little or no WML. The relationship between the severity of WML and subjective cognitive failures was present for periventricular and subcortical WML. CONCLUSIONS: WML are associated with subjective cognitive failures and in particular with reporting progression of these failures, even in the absence of objective cognitive impairment.     

缺血性脑损害对帕金森病运动症状影响的研究

目的：探讨静止性脑梗死(SCl)和脑白质损害(WML)对帕金森病(PD)运动症状的影响。方法：选取无中风史、头颅CT检查末见异常,年龄和病程配比的PD患者,观察3年后头颅MRI显示的SCl及WML的发生率及其对PD的运动功能的影响。结果：伴随高血压、糖尿病的PD患者较无伴随疾病者SCI及WML的发生率明显增高(P＜0．05),出现SCI及WML患者的运动功能评分较无SCI及WML患者明显增加(P＜0．01)。结论：预防脑缺血损害对延缓PD病情进展、控制症状具有重要的临床意义。     

脑白质病变认知障碍的危险因素研究

目的研究缺血性脑白质病变患者认知功能障碍的发病率及相关危险因素。方法收集75例脑白质病变(white matter lesions,WML)患者的人口学资料和血管危险因素,并进行认知功能评定,将病例分为认知障碍组和对照组,2组对比研究,探讨WML患者认知障碍的可能危险因素。结果 75例患者中44例(58.7%)出现了不同程度的认知功能障碍。Logistic回归分析显示WML患者发生认知功能障碍与高血压(OR 4.050,95%CI 1.309～12.526)、糖尿病(OR 3.820,95%CI 1.103～13.231)和年龄(OR 1.133,95%CI 1.023～1.255)有关。结论较高比例WML患者可出现认知功能障碍,高血压、糖尿病和老龄与认知功能障碍的发生关系密切。     

Neuropathology of white matter lesions in vascular cognitive impairment

The white matter is an important locus for tissue damage in vascular cognitive impairment and white matter lesions often dominate over gray matter changes. The spectrum of ischemic white matter lesions histopathologically represents focal and diffuse lesions, the most common form being the combination of both, in varying proportions. In the combined pathology, the diffuse lesion represents a gradient zone of damage towards surrounding normal tissue and may hold over 200 times the volume of an identified focal lesion, the lacunar infarct. Pathogenetically, the focal lesion results from the acute reaction to regional ischemia, while the diffuse white matter lesion represents the adjustment to altered perfusional and physiological conditions within the tissue.     

White-matter lesions on CT in Alzheimer patients: relation to clinical symptomatology and vascular factors

Fifty-four patients with Alzheimer's disease (AD) were examined for white-matter lesions (WMLs) using computerized tomography. WMLs were more frequent in late-onset AD (LAD) (26/34-76%) than in early-onset AD (EAD) (5/20-25%) (p less than 0.0001), in AD without parietal predominance (10/11-91%) (p less than 0.005) than in AD with parietal predominance (5/15-33%), and in AD with confusional symptoms (11/12-92%) than in AD without confusional symptoms (4/14-29%) (p less than 0.001). The supine systolic blood pressure was higher in AD with WMLs (151 +/- 20) than in AD without WML (139 +/- 22) (p less than 0.05). AD patients with WMLs, but not those without WMLs, had a higher mean albumin ratio (7.5 +/- 2.7) than healthy controls (5.7 +/- 2.1) (p +/- 0.005). The finding of less focal (= less parietal) symptomatology in AD with WMLs than without WMLs suggests clinical significance of WMLs in AD, while the relations between blood pressure, BBB function and WMLs support the hypothesis of a vascular pathogenesis.     

Fibrinogen gene haplotypes in relation to risk of coronary events and coronary and extracoronary atherosclerosis: the Rotterdam Study

Fibrin network structure has been correlated with coronary disease. Fibrinogen gamma and alpha (FGG and FGA) gene haplotypes (chromosome 4q28) may be associated with fibrin network structure, and thereby with rigidity of the fibrin clot and sensitivity of the fibrin clot to the fibrinolytic system. Through these mechanisms they may influence risk of cardiovascular disease. We set out to investigate the relation between combined fibrinogen FGG and FGA gene haplotypes, representing the common variation of the fibrinogen FGG and FGA genes, coronary events and measures of coronary and extracoronary atherosclerosis. The study was embedded in the Rotterdam Study, a prospective population-based study among men and women aged >or=55 years. Common haplotypes were studied using seven tagging SNPs across a 30-kb region with the FGG and FGA genes. Incident coronary events were registered, and carotid intima-media thickness, carotid plaques, ankle-arm index, aortic calcification and coronary calcification were assessed. Seven haplotypes with frequencies >1% covered 97.5% of the genetic variation. In 5,667 participants without history of coronary heart disease (CHD), 733 CHD cases occurred during a median follow-up time of 11.9 years. Fibrinogen gene haplotypes were not associated with coronary events. Fibrinogen gene haplotypes did not show a consistent association with measures of coronary and extracoronary atherosclerosis. In conclusion, fibrinogen FGG and FGA gene haplotypes are not associated with coronary events, coronary atherosclerosis or extracoronary atherosclerosis. Confirmation of these findings by future population-based studies is warranted.