Introduction

Stroke and dementia are tightly related. About 1 patient in 10 already has dementia when stroke occurs, 1 in 10 will develop dementia after a first-ever stroke, and this percentage increases dramatically to one in three in patients with stroke recurrence [1]. In the population currently living in Western countries, of three persons at least one will develop dementia, stroke, or both [2]. Stroke is the leading cause of physical disability in adults: of 1 million inhabitants, 2 400 patients have a stroke every year, of whom more than 50% will die or become dependent 1 year later [3]. Dependency after stroke is often due to dementia. Even in stroke survivors who are independent, mild cognitive or behavioral changes may have consequences on familial and professional activities [4]. In Europe, 6.3 million people are affected by dementia [5]. The prevalence of dementia increases with advancing age and is estimated to affect more than 30% of people over 80 years of age. Cerebrovascular diseases account for most cases of older onset dementia [6] and the pathological correlates are more likely to be found when compared to the neurofibrillary tangle and cortical beta amyloid plaques together [7]. The cognitive consequences of stroke carry an associated burden of increased mortality [8, 9], recurrence [10], institutionalization [11], dependency [12], and delayed discharge [13]. Moreover, dementia is one of the largest contributors to all causes of morbidity in Europe, as measured by disability-adjusted life years [14].

The relationship is more complex than being just a coexistence of two frequent disorders. Besides being a potential cause of dementia, stroke negatively influences the time course of Alzheimer’s disease (AD). Post-stroke dementia (PSD) is a significant independent predictor of stroke recurrence [10] and is associated with impaired survival after stroke [15]. Moreover, stroke and Alzheimer’s disease share many risk factors, such as increasing age, arterial hypertension, and APOE4 [5]. Reciprocally, dementia may increase stroke risk [16]. The prevalence of stroke and of dementia are likely to increase in the next years, because of the decline in mortality after stroke [17] and aging of Western populations [18]. Therefore, the burden of stroke-related dementia is also likely to increase in the future [4].

Definitions

Post-stroke dementia (PSD) includes any dementia that occurs after stroke, irrespective of its cause, i.e. vascular, degenerative, or mixed [4]. The concept of PSD is useful for patients who are followed up after a stroke, before an extensive diagnostic workup makes possible a classification into vascular dementia (VaD), degenerative dementia (especially AD), and mixed dementia, i.e. dementia due to the coexistence of vascular lesions of the brain and neurodegenerative lesions, usually of Alzheimer type, both types of lesions being not necessarily severe enough to induce dementia when isolated.

VaD refers to the spectrum of cognitive decline causally associated with brain lesions of vascular origin. The term “VaD” cannot be used for all patients who have had a stroke and are demented, because many of them have AD.

Limits of This Review

This chapter will not cover: (1) cognitive impairment no dementia, but we should bear in mind that the cognitive burden of stroke is severely underestimated, cognitive impairment no dementia being three times more frequent in patients who have had a stroke than in stroke-free controls [19]; and (2) dementia associated with apparently purely “silent” vascular lesions of the brain (silent infarcts, microbleeds, and leukoaraiosis), i.e. brain lesions presumably of vascular origin that occur in the absence of clinical symptoms of stroke or transient ischemic attacks. Therefore, our review will focus only on dementia that occurs – or was already present – in patients who have had clinical symptoms of stroke.

Search Strategy

References for this review were identified by searches of Medline between 1970 and November 30, 2017 and references cited by relevant articles. Manuscripts were selected on the basis of the presence of the following key words in the title: (1) dementia or cognition or cognitive decline or cognitive impairment or cognitive dysfunction or Alzheimer; plus (2) stroke or cerebrovascular or infarct or hemorrhage or hemorrhage or ischemia or ischemia or white matter or leukoaraiosis or leukoaraiosis or microbleed. We reviewed only manuscripts, with abstracts published in English, French, German, Italian, or Dutch. Abstracts and reports from meetings were not included. The final reference list was generated based on originality and relevance to the topics covered in the review (dementia in patients who have clinical signs of stroke). Due to the limitation of 50 references for this chapter, we finally gave priority to the most recent references, and we used two previous reviews where one of us contributed [4, 20] anytime it was possible, to prevent citation of more than 50 references, especially in the section on factors influencing the occurrence of dementia after stroke. Therefore, many relevant references published previously can be found in our previous reviews [4, 20], and are not cited in this chapter.

Descriptive Epidemiology of Dementia Occurring after Stroke

Relative Risk of Dementia after Stroke

A history of stroke approximately doubles the risk of dementia incidence in the population aged >65 years, but people who survived without dementia to 85 years of age are not at increased risk of dementia incidence compared with their stroke-free, age-matched subjects [26]. The excess risk of dementia increases in studies on incidence compared to studies on prevalence of PSD. This likely reflects both the higher risk of dementia within the first few months after stroke and the higher rate of mortality in individuals with stroke and dementia. In the first year after stroke, patients have a 9-fold increased risk of incident dementia when compared with controls. The excess rate of incident dementia in stroke patients vs. controls persists in the following years, but after the first year, it decreases to two to four times the background risk. In the Framingham study, the results were similar 10 years after stroke, after adjustment for age, gender, education level, and exposure to individual risk factors for stroke [27]. In the Rochester study, the risk of AD was doubled after 25 years. A study where stroke was not associated with an increased risk of dementia [28] was actually conducted in non-aphasic patients, with mild first-ever strokes, and only 1 year of follow-up, i.e. the best conditions to minimize the incidence of new-onset dementia. Finally, the results of hospital- and community-based studies can be summarized as follows: (1) stroke doubles the risk of dementia; (2) the attributable risk is the highest within the first year after stroke, then declines, and the relative risk of dementia remains stable around two to four times; and (3) the risk of delayed dementia (including AD) remains also doubled 10 years and more after stroke.

Factors Influencing the Occurrence of Dementia after Stroke

Determinants of post-stroke dementia that have been found in at least two independent studies, or have been identified recently, are listed in Box 16.1.

Demographic and Medical Characteristics of the Patient

The most important demographic predictors of dementia after stroke, shared with pre-stroke dementia, are older age (weighted mean difference = 5.1, 4.6–5.7, years p <0.0001), low educational level, prior cognitive decline, and premorbid disability [29]. Being Caucasian, as opposed to being Black or Hispanic, is protective. Concerning the gender, female sex was not generally a significant independent predictor of post-stroke dementia when multivariate adjustment was done for age and other risk factors.

Among vascular risk factors, diabetes mellitus and atrial fibrillation are independent predictor factors of PSD [1]. Myocardial infarction was found to be an independent risk factor for dementia after stroke in several studies [4], but a meta-analysis [1] did not confirm the result. Arterial hypertension, ischemic heart disease, cholesterol, prior transient ischemic attack (TIA), and smoking were not associated with PSD [1]. The influence of alcohol consumption on PSD remains unproven [4]. All these vascular factors were associated with pre-stroke dementia, but not with post-stroke dementia, suggesting that the development of PSD is more dependent on stroke-related factors. Nonetheless, the results concerning the vascular risk factors should be interpreted with caution because they could still be confounded with stroke-related factors, including severity of stroke, mortality, and recurrence. Results on ApoE4 genotype are inconsistent. ApoE4 genotype is independently associated with an increased risk of dementia after stroke in some studies [30], but not all. In patients surviving an ICH, presence of disseminated superficial siderosis is associated with an increased risk of dementia [25].

Pre-existing Silent Brain Lesions in Stroke Patients

Silent infarcts, i.e. cerebral infarcts seen on CT or MRI scans that have never been associated with a relevant neurological deficit, are associated with an increased risk of dementia after stroke [4]. Their influence is more important when the follow-up is longer: in the Lille study, silent infarcts were associated with dementia after stroke at year 3 [30], but not at year 2, and in the Maastricht study silent infarcts were independently related with dementia after 12 months, but not after 1 and 6 months [31]. Stroke patients with associated silent infarcts seem to have steeper decline in cognitive function than those without, but this decline might be confined to those with additional silent infarcts after baseline.

Patients with small-vessel disease (SVD) have various degrees of brain atrophy, which is considered to be part of the SVD spectrum [20]. The underlying cause is the coexistence of the aging process, degenerative mechanism, and subcortical vascular changes [20]. Global cerebral atrophy is associated with a higher risk of dementia after stroke [4, 20], even in CADASIL [32], a disease that occurs early in life, where coexistent degenerative disorder is very unlikely. In CADASIL, a model of pure vascular dementia, the imaging parameter that is the most closely associated with dementia is cortical atrophy [32].

Medial temporal lobe atrophy (MTLA) represents a stronger predictor of pre-stroke dementia than post-stroke dementia, suggesting a major role in primary degenerative brain pathology. MTLA clearly differentiate demented from non-demented patients after a first-ever ischemic stroke, even after exclusion of patients who had pre-stroke cognitive impairment [4]. Stroke patients with MLTA may have pre-clinical AD, which is clinically revealed by stroke [33]. However, MTLA is not specific to AD, as it has also been observed in VaD [4, 5].

Presence and severity of leukoaraiosis are independent predictors of both pre-stroke and post-stroke dementia [33]. In multivariate models, leukoaraiosis remained predictive of PSD. Nonetheless, potential confounding factors are higher stroke severity and recurrence, associated with leukoaraiosis and the coexistence with neuroimaging correlates of small-vessel disease (cerebral atrophy, lacunar infarcts) [34].

Brain microbleeds (BMBs) are related to cerebral amyloid angiopathy, hypertension, and atherosclerosis [35]. They are frequent in ischemic stroke patients [36], especially those with intracerebral arteriolopathies [35], and in patients with VaD and a lower degree AD [36]. BMBs are generally considered clinically silent, although recent evidence suggests that they may contribute to such clinical deficits as emotional lability in stroke [37]. Moreover, BMBs are also indicators of underlying brain vascular pathology, with consequences on executive dysfunction and cognitive decline after stroke [38, 39]. In a recent study the authors showed that the absence of BMBs may be associated with a higher likelihood of reversion from cognitive impairment no dementia phenotype after stroke [37]. However, the question of their influence on the risk of post-stroke dementia has never been systematically addressed and further study with large sample size is required to explore the effect of cerebral microbleed location on cognitive functions after stroke.

In patients with ICH, cortical atrophy, microbleeds and older age are the major risk factors for the occurrence of dementia after a few years of follow-up [25].