Stroke is one of the leading causes of disability in the Western world. According to the Global Burden of Disease Study in 2010 the stroke incidence worldwide was around 17 million persons per year, with 33 million people being still alive after stroke, with about 70 % of all stroke patients staying with residual symptoms [
1]. Stroke is the second most frequent cause of death, after coronary artery disease [
2]. As a result of the aging population, this number will probably increase steadily in the next decades [
3]. At the same time, case fatality rates are declining due to better acute treatment. Therefore, more and more individuals will need to learn how to deal with the residual disabilities and handicaps [
1]. Frequent impairments after stroke are cognitive impairments and neuropsychiatric syndromes, including depression and apathy [
4,
5] which have an impact on long-term prognosis (higher mortality and more disability) and quality of life (QoL) of stroke survivors [
6,
7].
Vascular cognitive impairment
Vascular cognitive impairment (VCI) describes the full spectrum from mild to severe cognitive impairment in people with cerebrovascular disease, including vascular mild cognitive impairment and vascular (or post-stroke) dementia (VaD) [
8]. Risk factors of VCI after stroke include event-related factors such as infarct severity, lesion volume, age, low education, history of diabetes or atrial fibrillation, and number of recurrent strokes [
9]. The risk for post-stroke dementia is known to be highest within the first year, with an estimated incidence rate of 20–30%, which is nine-times the general population’s risk [
9].
It has been suggested that both vascular and neurodegenerative pathologies contribute to post-stroke VCI [
10]. Cognitive impairments can be the result of strategic infarcts, but (pre-existing) white matter hyperintensities (WMH) and atrophy of the medial temporal lobes can contribute too, and they probably interact with each other, though the nature of these interactions is not well understood [
11]. In addition, a higher risk for VCI has been reported in carriers of the Apolipoprotein E (ApoE) ε4 allele, which is the major genetic risk factor for Alzheimer’s disease (AD) dementia [
12]. Indeed, evidence accumulates that AD and VaD should not be regarded as mutually exclusive diagnoses, but rather as a continuum with pure AD and VaD at its extremes, and most people showing mixtures of both type of pathologies [
13]. While the dominating view is that vascular changes work as a catalyst of primary neurodegenerative changes in AD it is largely unknown whether the opposite is true for VCI, i.e. whether AD-related changes work as a catalyst for post-stroke dementia.
Next to neurodegeneration, neuro- and vascular inflammation might contribute to VCI by partly mediating the pathophysiology underlying VCI as part of a final common pathway [
14]. Following stroke, increased auto-immune activity is a common response, and it has been shown that up-regulated inflammation markers like C-reactive protein (CRP), as a consequence of a prolonged auto-immune response, relate to poor prognosis. This includes a higher risk of additional future strokes and mortality, but also more severe VCI [
15,
16]. Other enzymes, molecules, and ligands (myeloperoxidase, soluble intercellular adhesion molecule, soluble vascular cell adhesion molecule-1, soluble E selectin, soluble P selectin and CD40 ligand) are involved in vascular inflammation as part of an inflammatory response to stroke, and have also been found to be increased in AD [
17‐
20]. Also, up-regulation of proinflammatory cytokines (interleukin-6 and tumor necrosis factor alpha) and proteins (high sensitivity CRP) are risk factors for both dementia [
21,
22] and cardiovascular disease [
23]. It is unknown whether similar inflammation mechanisms are involved in cognitive deterioration in VCI, and therefore, research is needed to investigate whether inflammation contributes to VCI independently or in joint action with other (e.g. neurodegenerative) factors.
Finally, genetic factors are also suggested to play a role in the pathogenesis of VCI, but in contrast to AD, evidence is still scarce. A genome-wide association study in VaD identified a novel genetic locus near the androgyn receptor, and this finding was replicated in two independent validation datasets [
24]. Polymorphisms and mutations on the genes coding for angiotensin-converting enzyme and methylenetetrahydrofolate reductase are risk factors for cardiovascular diseases and might be related to the development of VaD, although this relationship is still controversial [
25]. For AD, several genetic risk loci are already identified next to ApoE, including clusterin (CLU), phosphatidylinositol binding clathrin assembly protein (PICALM), and encoding complement component [3b/4b] receptor 1 (CR1) [
26], but their effects are generally small (see
http://www.alzgene.org). Whether they contribute to post-stroke dementia is not known.
Post-stroke depression
Depression is a common neuropsychiatric syndrome following stroke. According to a recent systematic review by Hackett et al. [
27], around one-third of the stroke survivors experiences depression in the first 3 months post-stroke, and studies with long-term follow-up have shown that it is often a chronic disorder, with a remitting-relapsing pattern [
28]. Patients with post-stroke depression (PSD) have worse functional recovery [
29], a higher risk for cognitive impairment [
7], and higher mortality risk [
30,
31].
Early studies implied that PSD is mainly associated with anterior lesions in the left hemisphere, however, a major systematic review and meta-analysis found no support for this ‘lesions location hypothesis’ [
32]. Vataja et al. [
33] suggested that lesions in fronto-subcortical regions in general are involved in developing PSD, often accompanied by impairments in executive functioning, leading to what has been called the ‘depression-executive dysfunction syndrome’. Other factors that have been associated with the development of PSD are cognitive impairment, stroke severity, physicial disability, and pre-stroke depression and anxiety [
7]. Diminished QoL and also low social support can both contribute independently to the severity of depression [
34]. A study by van Mierlo et al. [
35] investigated the association between a broad range of psychological factors and PSD with a multivariable logistic regression analysis. They showed that more passive coping and more helplessness, less acceptance and less perceived benefits were all significantly and independently associated with symptoms of post-stroke depression. Furthermore, fatigue after stroke has been associated with PSD, although not all patients with fatigue develop symptoms of depression and vice versa [
28].
Neuroinflammation might also play a role in the underlying mechanisms of PSD. Levels of CRP, soluble E selectin, CD40 ligand, interleukin-6, tumor necrosis factor alpha, and high sensitivity CRP are deregulated in patients diagnosed with major depressive disorder [
14,
18,
22,
23,
36‐
38]. In addition, high plasma levels of neopterin are found in people with depression, and might predict the development of PSD [
39]. Markers of endothelial function might be important as well, since increased expression of soluble intercellular adhesion molecule and soluble vascular cell adhesion molecule-1 are associated with depression [
40‐
43]. Although several inflammation markers have been related to symptoms of depression, studies examining these associations in PSD specifically are relatively scarce. Some studies found an elevation in interleukin-6 and tumor necrosis factor alpha in PSD [
44]. Recently, a study by Tang et al. [
39] showed an association between elevated serum levels of neopterin in the acute phase after stroke and PSD at 6-month follow-up.
High plasma levels of homocysteine are known to increase the risk for cerebrovascular disease, but have also been associated with depressive disorders. Increased levels of homocysteine result in cerebrovascular disease and a deficiency in monoamine neurotransmitters, which might lead to a depressed mood [
45]. Homocysteine, folate and vitamin B12 are all involved in methylation reactions that are necessary for monoamine neurotransmitter production, but also the production of phospholipids and nucleotides. A deficiency in folate and vitamin B12 has also been associated with depressive disorders [
46].
Post-stroke apathy
Apathy has been defined as a disorder of diminished motivation, characterized by lowered initiative, restricted engagement in social interactions and activities, diminished cognitive activities, and lack of emotional response [
47]. It was traditionally seen as a symptom of other syndromes (e.g. depression and dementia), but mounting evidence suggests that it might be an independent syndrome with a different etiology [
48‐
50]. Post-stroke apathy (PSA) is as frequent as PSD, with a mean prevalence rate of 34.6 % at 4 months post-stroke [
5]. However, PSA gained relatively less attention in research in comparison with PSD, and most research focuses on the difference between the two.
While PSD is suggested to be associated with left anterior lesions [
51,
52], PSA has been associated with right hemispheric subcortical lesions, particularly in the basal ganglia and in the anterior cingulate circuit which is involved in motivational processes [
53‐
55]. Other factors associated with PSA are older age, lower education, and severity of VCI [
4,
5,
51,
56]. Furthermore, both PSD and PSA have been associated with poor functional recovery and low QoL [
5,
29]. Overall, lack of longitudinal studies, differences between time of measurement after stroke (acute phase/chronic phase), and lack of studies with a sufficient sample size make it difficult to interpret study results.
In conclusion, several factors play a role in the development of VCI, PSD, and PSA. However, most studies investigated the underlying mechanisms in isolation and did not take into account how several factors interact with each other. The Cognition and Affect after Stroke, a Prospective Evaluation of Risks (CASPER) study incorporates a broad range of psychosocial, blood and neuroimaging markers to be able to study their role alone and in combination with each other to predict individual differences in the onset and course of the cognitive and neuropsychiatric consequences of stroke.
Study aims
The primary aim of CASPER is to identify stroke-related, cerebrovascular, neurodegenerative, (epi)genetic, endothelial and inflammation markers that are associated with VCI, PSD, and PSA in patients with ischemic or hemorrhagic stroke. The secondary aims are to investigate how the above-mentioned markers interact with each other, and to determine if patients with apathy and depression after stroke differ in pathogenesis, course, and outcome (e.g. functional outcome, neurocognitive performance, quality of life).
The main research questions are:
1.
Are stroke-specific, additional vascular, neurodegenerative, inflammatory or genetic markers a) associated with VCI at 3 months after stroke and b) predictive for its course over 12 months?
2.
Are stroke-specific, additional vascular, neurodegenerative, inflammatory or genetic markers a) associated with PSD and PSA at 3 months after stroke and b) predictive for their course over 12 months?
3.
Do the above-mentioned markers interact on VCI, PSD, and PSA outcome?
4.
Which psychosocial factors are associated with the development of VCI, PSD, and PSA?
5.
Do PSA and PSD differ in their pathogenesis, cognitive profile, course, and outcome?