Search

White matter hyperintensity (WMH) shape has been associated with the severity of the underlying brain pathology, suggesting it is a potential neuroimaging marker of WMH impact on brain function.In 563 patients with vascular disease (58 +/- 10 years), we examined the relationship between WMH volume, shape, and cognitive functioning. WMH volume and shape were automatically determined on 1.5T brain MRI data. Standardized linear regression analyses estimated the association between WMH volume and shape (concavity index, solidity, convexity, fractal dimension, and eccentricity) and memory and executive functioning, adjusted for age, sex, educational level, and reading ability.Larger WMH volumes were associated with lower executive functioning Z-scores ( b (95%-CI):-0.09 (-0.17;-0.01)). Increased shape complexity of periventricular/confluent WMH associated with lower exec-utive functioning (concavity index + 1SD:-0.13 (-0.20;-0.06); solidity-1SD:-0.09 (-0.17;-0.02)) and lower memory function (fractal dimension + 1SD:-0.10 (-0.18;-0.02)). Of note, the association between concav-ity index and executive functioning was independent of WMH volume (-0.12 (-0.19;-0.04)). Our results suggest that WMH shape contains additional information about WMH burden, not other-wise captured by WMH volume.(c) 2022 The Author(s). Published by Elsevier Inc. This is an open access article under the CC BY license ( http://creativecommons.org/licenses/by/4.0/ )

Introduction: It has been hypothesized that carotid artery stenosis (CAS) may lead to greater atrophy of subserved brain regions; however, prospective studies on the impact of CAS on progression of hemispheric brain atrophy are lacking. We examined the association between CAS and progression of hemispheric brain atrophy. Methods: We included 654 patients (57 ± 9 years) of the SMART-MR study, a prospective cohort study of patients with manifest arterial disease. Patients had baseline CAS duplex measurements and a 1.5T brain MRI at baseline and after 4 years of follow-up. Mean change in hemispheric brain volumes (% of intracranial volume [ICV]) was estimated between baseline and follow-up for left-sided and right-sided CAS across three degrees of stenosis (mild [≤29%], moderate [30–69%], and severe [≥70%]), adjusting for demographics, cerebrovascular risk factors, and brain infarcts. Results: Mean decrease in left and right hemispheric brain volumes was 1.15% ICV and 0.82% ICV, respectively, over 4 years of follow-up. Severe right-sided CAS, compared to mild CAS, was associated with a greater decrease in volume of the left hemisphere (B = −0.49% ICV, 95% CI: −0.86 to −0.13) and more profoundly of the right hemisphere (B = −0.90% ICV, 95% CI: −1.27 to −0.54). This pattern was independent of cerebrovascular risk factors, brain infarcts, and white matter hyperintensities on MRI, and was also observed when accounting for the presence of severe bilateral CAS. Increasing degrees of left-sided CAS, however, was not associated with greater volume loss of the left or right hemisphere. Conclusions: Our data indicate that severe (≥70%) CAS could represent a risk factor for greater ipsilateral brain volume loss, independent of cerebrovascular risk factors, brain infarcts, or white matter hyperintensities on MRI. Further longitudinal studies in other cohorts are warranted to confirm this novel finding.

Objectives: Stroke is the second most common cause of death and a major cause of disability. Besides the physical consequences, depressive symptoms are frequent in the aftermath after stroke. Every year, approximately 15 million stroke survivors worldwide are at risk of developing post-stroke depression. In this study we describe the natural course of depressive symptoms in stroke patients over a long period of time post stroke and identify associated determinants. Materials and methods: From the Second Manifestations of ARTerial disease-Memory, depression and aging (SMART-Medea) study, an observational prospective cohort study, we selected patients with cerebrovascular disease, and used the biannually collected data of the Patient Health Questionnaire-9 for depressive symptoms. A score of >10 indicated the presence of depressive symptoms. A multinomial logistic regression analysis was used to identify prognostic determinants for courses of depressive symptoms after stroke. Results: During a mean follow-up time of 7.9 years, 62% of the 172 participants was never depressed, 19% had a single episode and 19% had recurrent depressive symptoms. Physical function was associated with increased risk for single episode and recurrent depressive symptoms (OR=1.06 [1.01-1.11]). OR's for social, mental and (vascular) comorbidities variables were not significant. Participants' physical function was only measured at baseline. Several relevant variables were not present in this dataset, including information about clinical events during follow-up. Conclusion: Nearly 40% of the participants are confronted with depressive symptoms on the long-term. Physical function plays a substantial part for stroke survivors in the development of these symptoms.

Late-life depression (LLD) increases risk for dementia and brain pathology, but possibly this is only true for one or more symptom profiles of LLD. In 4354 participants (76 ± 5 years; 58% female) from the Age, Gene/Environment Susceptibility (AGES)-Reykjavik Study, we identified five LLD symptom profiles, based on the Geriatric Depression Scale-15 (no LLD (57%); apathy (31%); apathy with emptiness (2%), mild LLD (8%) and severe LLD (2%)). Cox regression analyses showed that severe LLD, mild LLD and apathy increased risk of dementia up to 12 years, compared to no LLD. Additionally, hippocampal volume loss and white matter lesion increase, were assessed on 1.5 T MR images, at baseline and after 5 years follow-up. Only severe LLD showed increased WML volume over time, but not on hippocampal volume loss. WML increase over time mediated partially the relation between mild LLD and dementia but not for the other symptom profiles. It appears that hippocampal atrophy and LLD are independent predictors for dementia incidence, whereas for mild LLD the risk for dementia is partially mediated by WML changes.

Background: Late-life depression (LLD) is related to an increased risk of developing dementia; however, the biological mechanisms explaining this relationship remain unclear. Objective: To determine whether the relationship between LLD and dementia can be best explained by the glucocorticoid cascade or vascular hypothesis. Methods: Data are from 4,354 persons (mean age 76±5 years) without dementia at baseline from the AGES-Reykjavik Study. LLD was assessed with the MINI diagnostic interview (current and remitted major depressive disorder [MDD]) and the Geriatric Depression Scale-15. Morning and evening salivary cortisol were collected (glucocorticoid cascade hypothesis). White matter hyperintensities (WMH; vascular hypothesis) volume was assessed using 1.5T brain MRI. Using Cox proportional hazard models, we estimated the associations of LLD, cortisol levels, and WMH volume with incident all-cause dementia, AD, and non-AD dementia. Results: During 8.8±3.2 years of follow-up, 843 persons developed dementia, including 397 with AD. Current MDD was associated with an increased risk of developing all-cause dementia (HR = 2.17; 95% CI 1.66-2.67), with risks similar for AD and non-AD, while remitted MDD was not (HR = 1.02; 95% CI 0.55-1.49). Depressive symptoms were also associated with increased risk of dementia, in particular non-AD dementias. Higher levels of evening cortisol increased risk of dementia, but this was independent of MDD. WMH partially explained the relation between current MDD and dementia risk but remained increased (HR = 1.71; 95% CI 1.34-2.08). Conclusion: The current study highlights the importance of LLD in developing dementia. However, neither the glucocorticoid cascade nor the vascular hypotheses fully explained the relation between depression and dementia.

BACKGROUND: Late-life depression (LLD) is related to an increased risk of developing dementia; however, the biological mechanisms explaining this relationship remain unclear.OBJECTIVE: To determine whether the relationship between LLD and dementia can be best explained by the glucocorticoid cascade or vascular hypothesis.METHODS: Data are from 4,354 persons (mean age 76±5 years) without dementia at baseline from the AGES-Reykjavik Study. LLD was assessed with the MINI diagnostic interview (current and remitted major depressive disorder [MDD]) and the Geriatric Depression Scale-15. Morning and evening salivary cortisol were collected (glucocorticoid cascade hypothesis). White matter hyperintensities (WMH; vascular hypothesis) volume was assessed using 1.5T brain MRI. Using Cox proportional hazard models, we estimated the associations of LLD, cortisol levels, and WMH volume with incident all-cause dementia, AD, and non-AD dementia.RESULTS: During 8.8±3.2 years of follow-up, 843 persons developed dementia, including 397 with AD. Current MDD was associated with an increased risk of developing all-cause dementia (HR = 2.17; 95% CI 1.66-2.67), with risks similar for AD and non-AD, while remitted MDD was not (HR = 1.02; 95% CI 0.55-1.49). Depressive symptoms were also associated with increased risk of dementia, in particular non-AD dementias. Higher levels of evening cortisol increased risk of dementia, but this was independent of MDD. WMH partially explained the relation between current MDD and dementia risk but remained increased (HR = 1.71; 95% CI 1.34-2.08).CONCLUSION: The current study highlights the importance of LLD in developing dementia. However, neither the glucocorticoid cascade nor the vascular hypotheses fully explained the relation between depression and dementia.

ObjectiveTo determine whether white matter hyperintensity (WMH) markers on MRI are associated with long-term risk of mortality and ischemic stroke.MethodsWe included consecutive patients with manifest arterial disease enrolled in the Second Manifestations of Arterial Disease–Magnetic Resonance (SMART-MR) study. We obtained WMH markers (volume, type, and shape) from brain MRI scans performed at baseline using an automated algorithm. During follow-up, occurrence of death and ischemic stroke was recorded. Using Cox regression, we investigated associations of WMH markers with risk of mortality and ischemic stroke, adjusting for demographics, cardiovascular risk factors, and cerebrovascular disease.ResultsWe included 999 patients (59 ± 10 years; 79% male) with a median follow-up of 12.5 years (range 0.2–16.0 years). A greater periventricular or confluent WMH volume was independently associated with a greater risk of vascular death (hazard ratio [HR] 1.29, 95% confidence interval [CI] 1.13–1.47) for a 1-unit increase in natural log-transformed WMH volume and ischemic stroke (HR 1.53, 95% CI 1.26–1.86). A confluent WMH type was independently associated with a greater risk of vascular (HR 1.89, 95% CI 1.15-3.11) and nonvascular death (HR 1.65, 95% CI 1.01–2.73) and ischemic stroke (HR 2.83, 95% CI 1.36-5.87). A more irregular shape of periventricular or confluent WMH, as expressed by an increase in concavity index, was independently associated with a greater risk of vascular (HR 1.20, 95% CI 1.05–1.38 per SD increase) and nonvascular death (HR 1.21, 95% CI 1.03–1.42) and ischemic stroke (HR 1.28, 95% CI 1.05–1.55).ConclusionsWMH volume, type, and shape are associated with long-term risk of mortality and ischemic stroke in patients with manifest arterial disease.

Collaborators (845): Astrid M. Vicente Free PMC article:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6369905/ Objective: To explore genetic and lifestyle risk factors of MRI-defined brain infarcts (BI) in large population-based cohorts. Methods: We performed meta-analyses of genome-wide association studies (GWAS) and examined associations of vascular risk factors and their genetic risk scores (GRS) with MRI-defined BI and a subset of BI, namely, small subcortical BI (SSBI), in 18 population-based cohorts (n = 20,949) from 5 ethnicities (3,726 with BI, 2,021 with SSBI). Top loci were followed up in 7 population-based cohorts (n = 6,862; 1,483 with BI, 630 with SBBI), and we tested associations with related phenotypes including ischemic stroke and pathologically defined BI. Results: The mean prevalence was 17.7% for BI and 10.5% for SSBI, steeply rising after age 65. Two loci showed genome-wide significant association with BI: FBN2, p = 1.77 × 10-8; and LINC00539/ZDHHC20, p = 5.82 × 10-9. Both have been associated with blood pressure (BP)-related phenotypes, but did not replicate in the smaller follow-up sample or show associations with related phenotypes. Age- and sex-adjusted associations with BI and SSBI were observed for BP traits (p value for BI, p [BI] = 9.38 × 10-25; p [SSBI] = 5.23 × 10-14 for hypertension), smoking (p [BI] = 4.4 × 10-10; p [SSBI] = 1.2 × 10-4), diabetes (p [BI] = 1.7 × 10-8; p [SSBI] = 2.8 × 10-3), previous cardiovascular disease (p [BI] = 1.0 × 10-18; p [SSBI] = 2.3 × 10-7), stroke (p [BI] = 3.9 × 10-69; p [SSBI] = 3.2 × 10-24), and MRI-defined white matter hyperintensity burden (p [BI] = 1.43 × 10-157; p [SSBI] = 3.16 × 10-106), but not with body mass index or cholesterol. GRS of BP traits were associated with BI and SSBI (p ≤ 0.0022), without indication of directional pleiotropy. Conclusion: In this multiethnic GWAS meta-analysis, including over 20,000 population-based participants, we identified genetic risk loci for BI requiring validation once additional large datasets become available. High BP, including genetically determined, was the most significant modifiable, causal risk factor for BI. info:eu-repo/semantics/publishedVersion

OBJECTIVE Metabolic syndrome (MetS) is a cluster of cardiovascular risk factors leading to atherosclerosis and diabetes. Diabetes is associated with both structural and functional abnormalities of the brain. MetS, even before diabetes is diagnosed, may also predispose to cerebral changes, probably through shared mechanisms. We examined the association of MetS with cerebral changes in patients with manifest arterial disease. RESEARCH DESIGN AND METHODS Cross-sectional data on MetS and brain MRI were available in 1,232 participants with manifest arterial disease (age 58.6 ± 10.1 years; 37% MetS). Volumes of brain tissue, ventricles, and white matter hyperintensities (WMH) were obtained by automated segmentation and expressed relative to intracranial volume. Infarcts were distinguished into lacunar and nonlacunar infarcts. RESULTS The presence of MetS (n = 451) was associated with smaller brain tissue volume (B −0.72% [95% CI −0.97, −0.47]), even in the subgroup of patients without diabetes (B −0.42% [95% CI −0.71, −0.13]). MetS was not associated with an increased occurrence of WMH or cerebral infarcts. Impaired glucose metabolism, abdominal obesity, and elevated triglycerides were individual components associated with smaller brain volume. Obesity and hypertriglyceridemia remained associated with smaller brain volume when patients with diabetes were excluded. Hypertension was associated with an increased occurrence of WMH and infarcts. CONCLUSIONS In patients with manifest arterial disease, presence of MetS is associated with smaller brain volume, even in patients without diabetes. Screening for MetS and treatment of its individual components, in particular, hyperglycemia, hypertriglyceridemia, and obesity, may prevent progression of cognitive aging in patients with MetS, even in a prediabetic stage.

Cerebrovascular disease refers to a wide variety of conditions that lead to pathological changes in the blood vessels of the brain. These blood vessel changes can result in brain abnormalities. Although the clinical application of magnetic resonance imaging has substantially increased the knowledge on cerebrovascular diseases and their impact on the brain, there is a lack of knowledge with respect to several brain abnormalities that include white matter hyperintensities of vascular origin, microinfarcts in the deep gray matter and brain atrophy. This thesis examines the detection, risk factors and relation to clinical outcomes of white matter hyperintensities (WMH) of vascular origin, microinfarcts in the deep gray matter and brain atrophy. Data was used from the Second Manifestations of ARTerial disease-Magnetic Resonance (SMART-MR) study, a prospective cohort study at the University Medical Center Utrecht with the aim to investigate risk factors and consequences of brain changes on MRI in patients with symptomatic atherosclerotic disease. In the first part, we examine advanced quantitative features of WMH on MRI and their relation to clinical outcomes. After developing an algorithm to extract information on quantitative features of WMH from brain MRI scans, we showed that a greater volume and a more irregular shape of WMH were related to an increased risk of mortality and ischemic stroke. In the second part, we focus on the detection, risk factors and relation to cognitive functioning of microinfarcts in the deep gray matter on ultra-high field 7 tesla MRI. We observed that these lesions could be reliably detected on 7 tesla MRI, were associated with markers of both large vessel and small vessel disease, and were related to poorer cognitive functioning. In the last part, we examined potential risk factors for increased brain atrophy. We found that a reduced cerebral blood flow (measured on brain MRI) and mild carotid atherosclerosis on ultrasound pose risk factors for increased brain atrophy. The findings of this thesis may potentially be used in the future to identify patients who are at an increased risk for ischemic stroke, mortality and brain atrophy based on their brain MRI scan.

People with dementia have problems with cognitive functions, including their memory. The risk of dementia is greater in people with vascular risk factors such as hypertension or diabetes mellitus. Underlying brain damage can often be visualized with a brain scan. In this thesis, we researched in people without dementia if vascular risk factors are associated with brain changes and if these changes are associated with cognitive functions that may precede dementia. Furthermore, we researched if these risk factors were associated with progression of cognitive decline in patients with dementia. We describe that vascular risk factors are associated with subfields of the hippocampus, an important brain structure for memory, but we did not find that specific subfields were vulnerable. We also researched the presence of small cavities in the hippocampus and found that these were not associated with vascular risk factors or cognitive functioning. Their presence is most likely due to normal anatomical variation of the hippocampus. In this thesis we also describe that if people with a history of vascular disease experience cognitive problems, this may be associated with small infarctions of the brain, but not with other brain changes such as shrinkage of brain tissue. These people performed less on cognitive tests at first, but after an average of eight years we did not find this difference in performance anymore. We also describe that vascular risk factors have no or limited influence on progression of cognitive decline in patients with dementia.

Cerebellovascular disease refers to a group of cerebellar conditions related to its blood supply. In part I, we assessed cerebellar infarcts in relation to vascular territories. First, we critically appraised the existing classification system of small cerebellar infarcts, and propose to classify small cerebellar infarcts according to anatomical location instead of presumed border zones in between perfusion territories. This is expected to improve clinicoradiological correlation and may allow for a more reliable and reproducible classification. Still, the holy grail in stroke medicine remains to link infarcts with the responsible diseased artery by direct imaging of involved perfusion territories. This brings us to our next objective, which was to develop an innovative imaging technique to visualise cerebellar arterial perfusion territories in vivo. In order to visualise the cerebellar PICA-perfusion territories, we studied 14 healthy subjects with super-selective ASL MRI. By labelling both vertebral arteries, we were able to distinguish the territories supplied by one vertebral artery (PICA) from those supplied by both vertebral arteries (AICA and SCA) and from the contralateral vertebral artery (contralateral PICA). We demonstrated the high variability in the extent of the PICA, but also showed that the medial posterior inferior cerebellar surfaces were invariably perfused by the PICA. Our next goal was to investigate the occurrence and topographical patterns of incidental cerebellar infarcts in a cohort of 636 patients with arterial disease from the SMART-Medea study. Unlike cerebellar infarcts studied in the symptomatic stage, small cerebellar infarcts proved to outnumber large cerebellar infarcts by a factor of almost 20. We also found that the overwhelming majority of cerebellar infarcts comprised small infarct cavities within the cerebellar cortex. These cavities will be the subject of part II of this thesis, which begins with a radiological-pathological validation study. In 40 whole cerebella scanned with 7T ex vivo MRI, we found that 20 out of 22 cerebellar cavities were located in the cortex, and these were therefore named cerebellar cortical infarct cavities. All cavities retrieved on histopathological examination were compatible with an ischaemic origin. Additionally, we translated our findings towards lower field-strengths (1.5T) in vivo. This allowed us to study the epidaemiology of cerebellar cortical infarct cavities in the 636 patients from the SMART-Medea study, and found a significant relationship with markers of atherosclerosis, imaging markers of atherothromboembolic cerebrovascular disease, and worse physical but not mental functioning. In our final study, we observed cerebellar cortical infarct cavities ≤ 1.5 cm in 16 of 46 patients with a recent vertebrobasilar TIA or stroke and a symptomatic vertebral artery stenosis ≥50% from the Vertebral Artery Stenting Trial. Since only one of these 16 patients was known with a prior history of vertebrobasilar TIA or stroke, cerebellar cortical infarct cavities should be added to the spectrum of common incidental brain infarcts detectible on routine MRI. Identification of cerebellar cortical infarct cavities on MRI not only increases the visible burden of brain infarcts, but also adds insights to the temporal and spatial distribution of brain infarcts.

Cardiovascular disease is a major health problem worldwide. Accumulating evidence suggests that cardiovascular disease and a high cardiovascular risk play an important role in the etiology of cognitive decline and dementia. As intermediates in this relation between cardiovascular disease and functional decline in the aging population, structural brain changes have been proposed. The first objective of this thesis was to estimate longitudinal changes in brain volumes, cerebral small-vessel disease, and cerebral blood flow on MRI and to investigate their interrelations in patients with manifest arterial disease. We observed that global brain atrophy tended to accelerate with older age and that that was more pronounced in men than in women. We showed regression of white matter lesions in younger patients, but progression of white matter lesions with increasing age, similar for men and women. The incidence of new brain infarcts also increased with age and was stronger in men than in women. Across the different cardiovascular disease categories we showed that brain atrophy and progression of cerebrovascular lesions differed. To further study the longitudinal relations between brain atrophy and cerebral small-vessel disease, we studied how cerebral blood flow, as an indicator of cerebral perfusion, was associated with these features of the aging brain. We found that cerebral perfusion was part of a circular pathway in the etiology of structural brain changes; cerebral hypoperfusion leads to brain atrophy – brain atrophy is associated with more cerebral small-vessel disease – cerebral small-vessel disease leads to decline of cerebral blood flow and so on. However, it is not completely clear where this pathway starts and whether cerebral hypoperfusion is the cause or the consequence of brain atrophy and progression of cerebral small-vessel disease. Our second objective was to investigate two possible modifiable risk factors for brain aging and to study the long-term effect of brain aging on cardiovascular morbidity and mortality in patients with manifest arterial disease. We found that the combined presence of signs of hypertensive target organ damage, as measures of chronic hypertension, was associated with progression of global brain atrophy and more decline in memory performance, but not with progression of cerebral small-vessel disease or decline in executive functioning. We also studied hemoglobin and hematocrit as two hemorheological variables, which are of influence on the regulation of cerebral blood flow. We showed that higher hemoglobin and hematocrit resulted in lower levels of baseline cerebral blood flow and a decline in cerebral blood flow over time. Finally, we showed that smaller total brain volume increased the risk of death by any cause and the risk of an ischemic stroke.

Cardiovascular disease is a major health problem worldwide. However, the mortality risk in patients with cardiovascular disease has decreased due to early detection of the disease and improved treatment possibilities. The downside of increased survival rates are higher rates of long-term functional disability. Cardiovascular disease and an increased cardiovascular risk are associated with loss of function such as cognitive dysfunction, motor dysfunction, and depression. Vascular damage on brain MRI, reflected in markers of small vessel disease, is increasingly recognized as potential underlying factor for age-related function loss that is frequently found in patients with cardiovascular disease. The present thesis aimed to gain more insight in the cross-sectional, but particularly in the longitudinal relationship between risk factors, MRI markers of small vessel disease, and functional disability. In the first part of the thesis we investigated the association between risk factors, MRI markers of small vessel disease, and cognitive decline. We found that potentially modifiable risk factors (e.g. diabetes mellitus and physical activity) may have small impact on slowing down cerebral vascular damage and cognitive dysfunction in middle-aged patients already burdened with vascular disease. Cognitive dysfunction is a slowly developing process that may follow a stepwise progression over time. MRI markers of small vessel disease may be more sensitive to detect the influence of modifiable risk factors and may precede differences in cognitive decline. In part II of the thesis we were interested in the relationship of subclinical features of small vessel disease on brain MRI with motor dysfunction. We performed an explorative study to examine the association of microstructural abnormalities in specific white matter tracts with motor dysfunction in patients with type 2 diabetes mellitus with and without cognitive impairment. We found that in a small group of older patients with type 2 diabetes mellitus with slightly impaired motor performance scores, microstructural abnormalities in the corpus callosum were associated with motor performance scores in the expected directions, although the results were not statistically significant. In part III of the thesis we investigated the course of depression in patients with cardiovascular disease. 30% of these patients had an intermittent or chronic course of depression. Furthermore, of the patients with a history of vascular disease, those with cerebrovascular disease most often showed a chronic course of depression. Cerebral small vessel disease, on top of existing cardiovascular disease contributes to depression. Depression is therefore an important clinical manifestation of both large (e.g. stroke) and small vessel disease in patients with high vascular burden. Patients with cardiovascular disease may require more careful clinical monitoring and management of depressive symptoms.

‘Cerebral small vessel disease’ (CSVD) is een ziekte van de kleine bloedvaatjes in de hersenen. In onderzoek wordt vaak gebruik gemaakt van MRI markers: witte stofafwijkingen en lacunaire infarcten. Beide markers komen vaak voor in de normale bevolking. Dit proefschrift onderzoekt 1) mogelijk andere behandelbare risicofactoren naast hypertensie, 2) de klinische relevantie van deze radiologische markers, en 3) de etiologische verschillen tussen deze markers. Er werd gevonden dat verhoogd homocysteïne geassocieerd is met aanwezigheid en toename van beide witte stofafwijkingen en lacunaire infarcten, maar ook met toename van hersenatrofie en cognitieve tekorten. Daarnaast bleek dat homocysteïne een effect heeft op de ontwikkeling van een systemische kleine-vaatjes-ziekte, waarvan cerebral small vessel disease een onderdeel is. Daarnaast geven witte stofafwijkingen en lacunaire infarcten een hoger risico op beroertes en overlijden. Bovendien hangen witte stofafwijkingen, in tegenstelling tot de huidige inzichten, samen met cognitieve functiestoornissen en verslechtering daarvan in álle onderzochte cognitieve domeinen. Ook werd aangetoond dat witte stofafwijkingen en lacunaire infarcten - en voornamelijk toenamen - geassocieerd zijn met toename van hersenatrofie. Met 7T MRI werd de perivasculaire distributie van witte stofafwijkingen gedemonstreerd. De aard van het bloedvaatje verschilt afhankelijk van de anatomische locatie. Ook bleken risicofactorenprofielen voor het ontwikkelen van lacunaire infarcten in diepe witte stof en basale kernen te verschillen. Concluderend kan gezegd worden dat 1) homocysteïne betrokken is bij de ontwikkeling van CSVD en een mogelijk veelbelovend therapeutisch doelwit is, 2) radiologische markers van CSVD wel degelijk klinisch relevant zijn en 3) dat radiologische markers waarschijnlijk etiologisch van elkaar verschillen.

In this thesis we investigated whether the experience of stressful life events and depression were related to early symptoms of Alzheimer’s disease and whether this relation could be explained by alterations in hypothalamic-pituitary adrenal (HPA) axis activity. To study this we used data from two large cohort studies, the Longitudinal Aging Study Amsterdam (LASA) and the Second Manifestation of ARTerial disease (SMART) study. First, we established the relation between stressful life events and long-term changes in HPA axis activity, by investigating the relation between life events and cortisol levels. Cortisol levels are a marker of HPA axis activity. In LASA, we found that early life stress was associated with lower levels of cortisol, whereas recent life events were associated with higher levels of cortisol. We found that older persons with high levels of cortisol had poorer memory performance, but that high levels of cortisol were not a risk factor for memory decline over a period of 4 years. However, in older persons with a genetic susceptibility for AD (apolipoprotein e4 carriers) we found that alterations in cortisol levels were associated with memory decline. In addition to the studies in LASA, we investigated in the SMART study whether stressful life events can lead to cognitive impairment via alterations in HPA-axis activity. We found no evidence for stress-related cognitive impairment, as the experience of life events was associated with better cognitive functioning. Moreover, the relation between stressful life events and cognitive functioning was not explained by HPA-axis activity. We further examined the relation between depression and hippocampal and entorhinal cortex volume and whether this relation could be explained by HPA-axis activity. We found a differential relation of age of onset of depression and hippocampal and entorhinal cortex volume; early-onset depression (before age of 50 years) was associated with smaller hippocampal volumes, whereas late-onset depression (after age of 50 years) was associated with smaller entorhinal cortex volume The relations between depression and brain atrophy were not explained by HPA axis activity. The findings of these thesis suggest that particularly late-onset depression is associated with smaller entorhinal cortex volume, which could be indicative of early symptoms of Alzheimer’s disease, whereas early-onset depression was only associated with moderate hippocampal volume decrease. We hypothesize that depression does not lead to brain volume loss; rather we think that late-onset depression and brain atrophy are both a result of a common causal factor, for instance Alzheimer’s disease. In case of early-onset depression, it is likely that smaller hippocampal volumes precede the onset of depression and could even be a risk factor for the onset of depression. To conclude, psychosocial stress and depression were related to alterations in HPA-axis activity and elevated cortisol levels were also associated with cognitive impairment and brain atrophy, but we found no proof that psychosocial stress and depression lead to cognitive decline and brain atrophy via alterations in HPA-axis activity.