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Keywords:

  • cerebrovascular disease;
  • cognitive impairment;
  • neuropsychology;
  • rehabilitation;
  • stroke

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Defining cognitive impairment
  5. Is there a distinct profile of cognitive impairment arising from stroke?
  6. Are stroke characteristics associated with the profile of cognitive deficits?
  7. Are there rehabilitation approaches that improve cognitive performance after stroke?
  8. Conclusion
  9. Acknowledgements
  10. References

Cognitive impairment after stroke is common and can cause disability with major impacts on quality of life and independence. There are also indirect effects of cognitive impairment on functional recovery after stroke through reduced participation in rehabilitation and poor adherence to treatment guidelines. In this article, we attempt to establish the following: ● whether there is a distinct profile of cognitive impairment after stroke; ● whether the type of cognitive deficit can be associated with the features of stroke-related damage; and ● whether interventions can improve poststroke cognitive performance. There is not a consistent profile of cognitive deficits in stroke, though slowed information processing and executive dysfunction tend to predominate. Our understanding of structure–function relationships has been advanced using imaging techniques such as lesion mapping and will be further enhanced through better characterization of damage to functional networks and identification of subtle white matter abnormalities. Effective cognitive rehabilitation approaches have been reported for focal cortical deficits such as neglect and aphasia, but treatments for more diffusely represented cognitive impairment remain elusive. In the future, the hope is that different techniques that have been shown to promote neural plasticity (e.g., exercise, brain stimulation, and pharmacological agents) can be applied to improve the cognitive function of stroke survivors.


Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Defining cognitive impairment
  5. Is there a distinct profile of cognitive impairment arising from stroke?
  6. Are stroke characteristics associated with the profile of cognitive deficits?
  7. Are there rehabilitation approaches that improve cognitive performance after stroke?
  8. Conclusion
  9. Acknowledgements
  10. References

To reduce the cognitive fallout from stroke, we must be able to characterize abnormalities in cognition, understand the underlying causes of cognitive impairment, and determine the efficacy of different treatment and rehabilitation approaches. In this review, we will mostly confine ourselves to clinically apparent stroke but will discuss some evidence from studies of asymptomatic cerebrovascular disease and white matter changes.

Defining cognitive impairment

  1. Top of page
  2. Abstract
  3. Introduction
  4. Defining cognitive impairment
  5. Is there a distinct profile of cognitive impairment arising from stroke?
  6. Are stroke characteristics associated with the profile of cognitive deficits?
  7. Are there rehabilitation approaches that improve cognitive performance after stroke?
  8. Conclusion
  9. Acknowledgements
  10. References

Cognition is not a unitary concept; it incorporates multiple domains, including attention (focusing, shifting, dividing, or sustaining attention on a particular stimulus or task), executive function (planning, organizing thoughts, inhibition, control), visuospatial ability (visual search, drawing, construction), memory (recall and recognition of visual and verbal information), and language (expressive and receptive). Classification is far from straightforward, as domains are not independent – for example, remembering a list of grocery items you have been told to buy is not just reliant on memory but also on attention and language. What constitutes a cognitive domain is unclear, with the following dimensions often incorporated: neglect (inattention to one side of space), agnosia (failure in object recognition), apraxia (disordered motor planning), abstract thinking (ability to use higher-order semantic information), and arithmetic. It is important to recognize the effects that different states of physiology and mood (e.g., fatigue, apathy, depression) can have on cognition, though these factors will not be reviewed here as they are modifiers rather than components of cognition. The accepted ‘gold standard’ for determining cognitive abnormality is a battery of neuropsychological tests covering various domains, with normative information used to indicate domain-specific deficits. Our focus will be on cognitive impairment, which includes the milder end of the cognitive dysfunction spectrum and not the more disabling dementia. In an Alzheimer-dominated landscape, the term dementia has become amnestically loaded, with a dementia diagnosis requiring memory impairment. Yet memory dysfunction is often not the most pronounced feature after stroke; only about half of those with vascular cognitive impairment exhibit amnestic signs [1]. A more useful framework for classifying poststroke cognitive deficits emphasizes cognitive impairment rather than dementia [2]. This classification, though, still entails reducing rich information gained from multiple cognitive assessments down to a coarse dichotomy. Ideally, we want detailed information on performance across various cognitive tasks, thus allowing insight into the severity of and interrelationships among deficits in different domains.

Is there a distinct profile of cognitive impairment arising from stroke?

  1. Top of page
  2. Abstract
  3. Introduction
  4. Defining cognitive impairment
  5. Is there a distinct profile of cognitive impairment arising from stroke?
  6. Are stroke characteristics associated with the profile of cognitive deficits?
  7. Are there rehabilitation approaches that improve cognitive performance after stroke?
  8. Conclusion
  9. Acknowledgements
  10. References

There is a substantial literature on domain-specific cognitive function after stroke. In an influential 1994 study, Tatemichi and colleagues identified a generalized profile of cognitive problems across all domains. Attention, memory, language, and orientation were most affected by stroke, yet patients also had marked deficits in visuospatial skills and abstract reasoning [3]. In 1998, a large European study yielded a similarly diffuse poststroke cognitive profile. Tasks of attention, visuospatial ability, and verbal fluency were the most affected, but language and memory performance was also down [4]. It is now thought that stroke tends to have greater deleterious impact on attention and executive function than on memory, but such a profile was not evident in these early studies. A possible explanation relates to experimental design. The above two studies compared hospital-based stroke patients with healthy volunteer controls and thus may have overestimated poststroke cognitive impairments, diminishing any domain-specific differences. In a community-based comparison of stroke patients with population controls, results fit more closely with current thinking. Patients were more frequently impaired than controls in spatial ability, executive function, attention, and language but were not more impaired in orientation or memory [5]. Other studies have reinforced the view that stroke-related cognitive problems are weighted more toward attention-executive dysfunction than memory dysfunction. Marked deficits in abstraction, executive function, and processing speed have been reported [6]. Population-based evidence suggests that a history of stroke is associated with a higher risk of nonamnestic [odds ratio (OR) = 2·85] than amnestic (OR = 1·77) cognitive impairment and is associated with every cognitive domain except memory [7]. Contributing evidence comes not only from stroke but from studies of other vascular changes. In a cohort of 164 Catholic nuns, priests, and brothers, the presence of one or more silent infarcts on autopsy was related most strongly with perceptual speed and least strongly with episodic memory [8]. Magnetic resonance imaging (MRI) data from elderly participants in the LADIS study indicated that the appearance of new lacunes is associated with decline in executive function and processing speed but not memory [9].

Speed of processing

Cognitive slowing is a common complaint after stroke, and a majority of patients exhibit marked slowness of information processing [4, 10]. Processing speed is clinically relevant, as it makes an independent contribution to functional outcome after stroke [11] and is independently predictive of dependency in stroke survivors [12]. While not typically considered a stand-alone domain, processing speed has a major influence on cognitive performance. Importantly, this influence is not consistent across different cognitive domains. It is possible that attention and executive deficits appear to predominate after stroke because these domains are more often tested using time-sensitive tasks (e.g., Trail-Making and verbal fluency) than the domains of memory or language. There is evidence to support this: when the block design task from the Wechsler Adult Intelligence Scale (WAIS) was time limited, 47% of stroke patients performed beyond two standard deviations below the control mean, compared with only 24% when there was no time limit [4]. We contend that the ‘typical’ poststroke cognitive profile should include deficits in processing speed alongside deficits in attention and executive function. The prominence of these domains appears to be unaffected by the length of time since stroke. In acute stroke, disorders in executive function were found to be particularly prevalent [13]. At one year poststroke, a majority of patients still had attention deficits, while deficits in language and memory were more likely to have resolved [14]. At five years poststroke, deficits were more pronounced in processing speed (z = −2·16) and executive function (z = −1·92) than in visual memory (z = −0·43) and verbal memory (z = −0·32) [11].

Memory function

Identifying the extent to which memory is compromised after stroke can be difficult. Ballard et al. [15] concluded that impairments of processing speed, attention, and executive function were the most pronounced after stroke, but the exclusion of patients with dementia meant memory impairment was unlikely to be prominent. Early studies on multi-infarct or vascular dementia focused on differentiating these entities from Alzheimer's disease. Data typically showed that vascular dementia patients had superior long-term memory but more frontal executive impairment than Alzheimer patients [16]. It is important to recognize, though, that such results do not imply spared memory in the vascular patients. More direct evidence for this sparing is the finding that memory performance of patients with cerebrovascular disease was much closer to a healthy elderly profile than an Alzheimer profile [17]. Of course, memory problems can manifest following stroke. The five-year progression of vascular cognitive impairment has been shown to include memory deficits [18]. The presence of sub-cortical infarcts in older people has been associated with lower episodic, semantic, and working memory performance [19]. Memory deficits, though, appear to be less prevalent than deficits in other cognitive domains, and when they do occur, they are likely to have a different genesis to those seen in Alzheimer patients. Recognition memory, which tests retention of information without effortful search and retrieval, may be less affected than noncued recall after stroke [4, 6], suggesting that the underlying cause may be less amnestic and more executive.

Are stroke characteristics associated with the profile of cognitive deficits?

  1. Top of page
  2. Abstract
  3. Introduction
  4. Defining cognitive impairment
  5. Is there a distinct profile of cognitive impairment arising from stroke?
  6. Are stroke characteristics associated with the profile of cognitive deficits?
  7. Are there rehabilitation approaches that improve cognitive performance after stroke?
  8. Conclusion
  9. Acknowledgements
  10. References

Many studies into this question rely on correlative evidence, associating stroke features and cognitive status in large cohorts. Early research indicated that cognitive impairment was most frequent after left anterior and posterior cerebral artery infarcts, and less frequent after vertebrobasilar artery infarcts [3]. Others have found that infarcts in the middle cerebral artery (MCA) are associated with greater likelihood of cognitive impairment [20]. Stroke in cortical regions increases the likelihood of cognitive dysfunction. In the acute stage of stroke, cognitive impairments were detected in 74% of patients with cortical stroke but in less than 50% of those with sub-cortical or infratentorial stroke [13]. Stroke etiology also plays a part in cognitive outcome: cortical deficits such as aphasia and neglect were more common after cardioembolic stroke than either large-vessel or small-vessel disease stroke [21].

In terms of more general stroke characteristics, a meta-analysis identified haemorrhagic stroke, left hemisphere involvement, and recurrence as the factors that predicted subsequent dementia [22]. Haemorrhagic stroke has been independently associated with cognitive deficits across multiple domains [13]. Lesions tend to be larger in cognitively impaired patients than in nonimpaired patients (27 vs. 9 cm3) [13], but this is neither surprising nor particularly informative as larger strokes are more likely to encroach upon cortical and other regions that support cognition. Left hemisphere bias in cognitive impairment is a common finding, though the reliance of many neuropsychological tasks on language ability is a confounding factor. Stroke recurrence has been linked to cognitive decline and was independently associated with incident dementia at two-year follow-up [23]. In terms of cognitive prognosis, lesion location was a useful predictor of domain-specific recovery, but lesion volume was an independent predictor of recovery only in visual memory [24]. Other studies have shown that lesion volume, while correlated with initial aphasia severity, was not associated with recovery in language [25, 26]. The impact of lesion laterality on cognitive recovery is unclear, with examples of right hemispheric superiority [27], left hemispheric superiority [28], and no difference [24].

Aphasia and neglect

In clinical practice, two of the most prominent focal cognitive deficits after stroke are aphasia and hemispatial neglect [29]. The relationship between type of aphasia or neglect and location of infarction is well described. The limitation to spoken output that is characteristic of Broca's aphasia is associated with damage in the left posterior, inferior frontal gyrus, in addition to other regions supplied by the upper division of the left middle cerebral artery [30]. Wernicke's aphasia, on the other hand, is characterized by fluent but relatively meaningless speech alongside poor language comprehension and is linked to damage in the left posterior, superior temporal gyrus [30]. In hemispatial neglect, the visuospatial component is linked to the right inferior parietal lobule, the visuomotor component to the right dorsolateral prefrontal cortex, and the object-centered component to the deep temporal lobe regions [31]. Structure–function evidence of this kind is often derived from lesion mapping, where lesions from a group of stroke patients with a particular cognitive deficit can be superimposed to determine the area of greatest overlap. This powerful technique employs group data while accounting for individual variability in brain structure. The problem is that while the mapping approach can work well for focal syndromes associated with lesions in circumscribed areas, more complex cognitive deficits such as executive dysfunction involve more widely distributed injury and more likely a broad network. Neuropsychological [32] and functional imaging [33] evidence indicates that executive processes are not limited to the frontal lobes but are sub-served by a distributed network of cortical, sub-cortical, and infratentorial areas. Even in the case of neglect, it has been argued that dysfunction of distributed cortical networks for attention provides a better account than structural damage to specific regions [34].

Diffuse neuronal dysfunction

There is a broad distinction between focal damage, which can lead to selective cognitive impairments, and diffuse neuronal dysfunction, which produces a more uniform profile of mental slowing, memory problems, and executive deficits [35]. Clouding the picture is the observation that certain strategic infarcts (e.g., genu of the internal capsule) can produce what clinically appears to be a diffuse cognitive syndrome [36]. Diffuse dysfunction typically results from underlying sub-clinical cerebrovascular disease, such as white matter disease, or an accumulation of small infarcts as in small-vessel disease [37]. Over the four years following stroke, higher load of white matter hyperintensities (WMHs) is strongly associated with dementia and cognitive decline [38]. Stroke patients with white matter lesions and silent infarcts were worse on cognitive tasks at baseline and two-year follow-up than those without this damage [39].

Though the damage is diffuse, it may be possible to identify some regional specificity in the relationship between white matter abnormalities and cognition. Slowed processing and attentional and executive impairments have been associated with the severity of WMHs in the internal capsule, caudate, and thalamus of stroke patients [40]. Lesions in these areas disrupt fronto-striato-thalamic circuits and thus impact upon dorsolateral prefrontal cortex and anterior cingulate, regions known to support attention and executive function. Cognitive impairment has been correlated with WMHs in the frontal lobes and internal capsule, with hyperintense lesions in the basal ganglia and thalamus most closely associated with neuropsychological performance [6]. Others have found that, while WMHs were associated with reduced mental speed, executive function, memory, and visuospatial ability, regional correlation was relatively weak [41]. The impact of small-vessel disease is not restricted to stroke: incidence of new lacunes in an elderly population has been linked to decline in executive function and processing speed [9].

Advanced imaging techniques, such as diffusion tensor imaging (DTI), can identify subtle abnormalities in axonal function that may be a marker for generalized cognitive impairment. Calculating functional anisotropy from DTI scans provides a metric for the integrity of white matter structures, with lower anisotropy reflecting greater diffusivity. Lower anisotropy has been identified in those with vascular cognitive impairment, even in regions without visible white matter abnormalities on conventional MRI [42]. In ischemic stroke patients, cognition appears more closely associated with anisotropy in frontal and parietal regions than in occipital and temporal areas [43]. We know that predicting cognitive outcome using the features of a focal lesion is imperfect; DTI offers the promise of increased explanatory power by determining the effects of altered connectivity between brain regions.

Hypoperfusion

Compromised blood flow is relevant to both focal and diffuse deficits. In ischemic stroke, focal cognitive deficits arise not just from the infarction itself but also from hypoperfusion in adjacent tissue. In the acute setting, aphasia and neglect are more closely associated with the volume of peri-infarct perfusion failure than the infarct itself [44]. White matter hyperintensities, thought to represent incomplete infarction, have been attributed to transient decreases in cerebral blood flow [45]. At the whole-brain level, the dynamic nature of information processing, attention, and working memory may be uniquely susceptible to dynamic changes in blood flow across widely distributed brain regions [46].

Perhaps the clearest evidence for a cerebral hemodynamic effect is in large-vessel disease, where loss of perfusion pressure to a cerebral hemisphere supplied by a blocked carotid artery induces a series of hemodynamic responses, including dilation of cerebral arterioles and increase of oxygen extraction fraction. TIA patients with recently symptomatic carotid artery occlusion who had single-hemisphere cerebral hypoperfusion had greater cognitive impairment than those without this hypoperfusion [47]. Hypoperfusion may also impact cognition through reductions in brain volume. Gray matter volume reductions have been identified in cognitively impaired ischemic stroke patients, predominantly in the thalamus [48]. With abnormalities in gray matter unrelated to the site of infarction, generalized hypoperfusion is a plausible mechanism.

Cardiac research also supports the idea of hypoperfusion-related cognitive dysfunction. Patients with global hemodynamic compromise arising from congestive heart failure have deficits in distributed processing skills, including attention, executive function, and memory [49]. In older patients with heart failure, memory performance was worse in those with lower left ventricular ejection fraction (<30%) [50]. Again, brain volume changes are potentially relevant; cognitive deficits arising from ischemic heart disease may be a result of reduced cerebral gray matter [51].

Sub-cortical stroke

Historically, damage to the cerebellum has been associated with disorders of motor coordination. While cerebellar stroke is unlikely to cause the classic cortical signs of aphasia or neglect [52], this does not mean the cerebellum is uninvolved in cognition [53]. Groups of patients with cerebellar damage, mostly with stroke etiology, have been shown to have deficits in visuospatial ability [54], verbal working memory [55], and across multiple domains including executive function and abstract reasoning [56]. There are anatomical grounds for expecting the cerebellum to play a role in cognition. While the cerebellum is a structurally distinct brain region, it is linked by neuronal circuits within the brain stem and has many projections toward associative brain areas [57]. Stroke in the basal ganglia can produce cognitive dysfunction. In a group of 12 patients with stroke confined to the basal ganglia, significant abnormalities were found in all domains tested (memory, attention, visuospatial, and language), though individual profiles were not presented [58]. The importance of the thalamus to cognition has been well documented. In a study of 10 patients with isolated thalamic lesions, deficits in long-term memory, executive function, and attention were associated with specific areas of the thalamus [59]. The thalamus is a good illustration of why lesion size is not everything – small but strategically placed lesions here can lead to severe cognitive impairments [60].

Neuropsychological assessment

Increased knowledge of structure–function relationships can inform our approach to neuropsychological assessment. There is now sufficient experience in different aspects of cerebrovascular disease that a long, comprehensive battery may not be necessary; rather, a tailored approach based on the nature of the disease (e.g., branch occlusion, carotid artery stenosis, and small-vessel disease) can be both clinically meaningful and cost effective [47, 61]. Of greatest relevance is the neuropsychological delineation of suspected cortical signs. For example, a brief, targeted neuropsychological assessment of cortical features such as neglect, spatial processing, and visuoconstructional function in a patient with a suspected right parietal stroke not only informs clinical diagnosis but also aids clinical decision making. The presence of cortical signs provides information about the likely stroke territory. This relates directly to probable stroke mechanism which, in turn, affects the preferred choice of treatment. A tailored assessment of this type can be particularly beneficial in an acute stroke setting where patient fatigue and attentional limitations often prevent lengthy, battery-type assessments. The fact that repair mechanisms, such as resolution of possible perfusion deficits [62], take their course in the days following stroke should not necessarily preclude early assessment. In striatocapsular stroke, for example, the cortical features that are diagnostic of this stroke sub-type are best identified in the first few days, after which they slowly resolve and become harder to detect. Timely characterization of cognitive impairment provides valuable prognostic information [24], assists in rehabilitation planning, and allows therapies to be targeted to specific cognitive domains.

Are there rehabilitation approaches that improve cognitive performance after stroke?

  1. Top of page
  2. Abstract
  3. Introduction
  4. Defining cognitive impairment
  5. Is there a distinct profile of cognitive impairment arising from stroke?
  6. Are stroke characteristics associated with the profile of cognitive deficits?
  7. Are there rehabilitation approaches that improve cognitive performance after stroke?
  8. Conclusion
  9. Acknowledgements
  10. References

Reducing the impact of poststroke cognitive impairment is an important goal. In addition to having a direct influence on the quality of life of patients and their caregivers, cognitive impairment after stroke is associated with higher mortality [63], greater rates of institutionalization [64], and higher health-care costs [65]. Cognition is important for recovery in other neurological domains – patients with higher cognitive status on admission to rehabilitation had better functional outcomes, even when relevant confounders were controlled [66]. Cognitive impairments can reduce a person's ability to understand task instructions, to plan and initiate self-directed activities, and to solve problem. The executive function of stroke patients in inpatient rehabilitation has been independently associated with the level of participation in rehabilitation [67].

Approaches to improving cognitive outcome after stroke can be classified as either compensatory or restorative. Compensatory approaches involve adapting the external environment to altered cognitive abilities. Characteristics of the external environment that help or hinder cognitive performance were identified in the Analysis of Cognitive Environmental Support tool [68]. One specific external strategy that has been tested is an electronic paging system. While found to be effective in compensating for everyday memory and planning problems after brain injury [69], maintaining these benefits over time may be difficult for stroke survivors [70]. Compensatory strategies can also be internally generated. Rather than attempt to restore reaction time to a normal speed, Winkens et al. [71] introduced a ‘time pressure management’ strategy: stroke patients were taught to compensate for mental slowness in real-life tasks by reorganizing the execution of sub-tasks that had a time pressure component. Their treatment group significantly outperformed controls on speed of performance on everyday tasks at three-month follow-up. Other cognitive rehabilitation approaches aim for the compelling goal of direct restoration of function. The realization that neural plasticity is present throughout life and can be influenced by training has generated hope in this area, but conclusive studies remain scarce. The strongest evidence of effectiveness is for treatment of focal cortical deficits. A review of evidence-based cognitive rehabilitation identified substantial evidence for cognitive-linguistic therapies to treat aphasia and for visuospatial rehabilitation to treat neglect after stroke, but effective treatments in other domains were lacking [72].

Domain-specific interventions

Originally used in the context of upper extremity and motor retraining after stroke, the principles of constraint-induced therapy have been applied to aphasia. Constraint-induced treatment protocols can improve functional communication in chronic aphasia after stroke [73]. There is also evidence that low-frequency repetitive transcranial magnetic stimulation (rTMS) can improve language abilities in patients with chronic nonfluent aphasia. The theory is that the stimulation modulates and inhibits overactivity in the right hemisphere homologous language sites, such as the inferior frontal gyrus. Significant improvements following rTMS have been reported in the picture naming [74], expressive language and auditory comprehension [75], and semantic fluency [76] of stroke patients with chronic aphasia.

In stroke patients with hemispatial neglect, using prism glasses to create an optical shift of the visual field to the right has been successful. The original 1998 study included patients in the first year after stroke and revealed improvements in sensorimotor and spatial function after a single prism adaptation [77]. More recent work has shown that prism adaptation also works in chronic stroke. In patients who were one to seven years poststroke and had persistent neglect, an eight-week intervention with prism glasses produced improved eye movements on the neglected side and improved standing center of gravity [78]. Prism adaptation may actually be best suited to the sub-acute and chronic stages of stroke when the nature of the neglect deficit has been established. Prism adaptation in acute stroke patients yielded some benefits on spatial tasks (line bisection and cancellation), but these benefits were not maintained at one month posttreatment [79]. It is likely that much of the improvement in both treatment and placebo control groups was due to spontaneous recovery.

Cochrane reviews have revealed the paucity of studies in poststroke cognitive rehabilitation for both memory deficits [80] and attention deficits [81]. Unlike the example of constraint-based therapy, the principles of task-specific training do not seem to translate from motor rehabilitation to cognitive rehabilitation. Repetition and rehearsal of the targeted cognitive task is insufficient to produce meaningful improvement. Results from one small stroke study (n = 12) indicated that teaching mnemonic strategies resulted in better memory performance, but improvements did not generalize beyond the trained memory tasks [82]. In a small trial (n = 27), a computerized training program had significant effects on alertness and sustained attention, but the benefits did not generalize to other attentional and cognitive functions [83]. In the years since the Cochrane reviews, one of the most promising studies was a randomized controlled trial of ‘attention process training’ in 78 stroke patients with attention deficits [84]. Postintervention change scores on the Integrated Visual Auditory Continuous Performance Test were superior in the treatment group, and this superiority was maintained at six-month follow-up.

Interventions for generalized cognitive impairment

Hypertension is an obvious treatment target. In the PROGRESS trial, active blood pressure lowering reduced the risk of cognitive decline (risk ratio = 19%), most likely by preventing the advance of additional lacunar infarcts [85]. This positive result, however, was not reproduced in the PRoFESS trial, where treatment with antiplatelet and antihypertensive therapy made no difference to cognitive outcomes [86]. Blood pressure control may also have a downside, given the association between hypoperfusion and cognitive performance. A quarter of a century ago, Meyer et al. [87] followed 52 multi-infarct dementia patients over two years. Among hypertensive patients, improved cognition was correlated with systolic blood pressure control within upper normal limits (135–150 mmHg) and cognition worsened if blood pressure was reduced below this level. As more direct evidence of this link, a pilot study showed that cortical reperfusion with temporary blood pressure increase for patients with large-vessel stenosis in the acute stage resulted in improved cognition, both in the short and longer terms [88].

Pharmacological agents can influence cognition. Normally used to treat depression, escitalopram has been found to benefit cognitive function in stroke patients [89]. Compared with patients who received placebo or problem solving therapy, those receiving escitalopram had improved global cognition on the RBANS (Repeatable Battery for the Assessment of Neuropsychological Status), particularly in memory. Rivastigmine, typically used in Alzheimer's disease, was tested in a randomized controlled trial among stroke patients with cognitive impairment but not dementia [90]. The treatment group exhibited significantly improved performance on verbal fluency for animals relative to controls. The results of these two studies and the previously cited study on attention process training [84], however, need to be interpreted with caution until successfully replicated. All three studies featured improvement in one or two cognitive measures in the context of multiple other cognitive outcomes that were not affected, and in each case there was an imbalance in baseline performance between the groups.

Increasing physical activity is another potential treatment; it has been shown to improve cognitive performance in the cognitively impaired [91], those at risk of Alzheimer's disease [92], and patients with multiple sclerosis [93]. Benefits seem to be greatest in cognitive speed and attention [94] and executive control [95]. This is important as these central cognitive processes provide the foundation for many other aspects of cognition. The relationship between physical and mental activity may also apply to stroke patients, but there is scant empirical evidence to date. In a recent review, only 12 studies were identified that employed physical activity interventions in stroke and had cognitive outcomes [96]. One of the few that had cognition as a primary focus found stroke patients exposed to an eight-week exercise program had improved information processing speed on a serial reaction time task relative to control patients [97]. Combining increased physical activity with mental challenges, sensory stimulation, and social interaction in an ‘enriched environment’ may contribute to improvements in cognition after stroke. Most of the current evidence for this comes from animals [98], but there are data from humans showing that listening to music early after stroke can enhance cognitive recovery [99]. Epidemiological studies have demonstrated the cognitive value of interactions with other people, using markers such as marital status and frequency of social activities [100, 101].

Conclusion

  1. Top of page
  2. Abstract
  3. Introduction
  4. Defining cognitive impairment
  5. Is there a distinct profile of cognitive impairment arising from stroke?
  6. Are stroke characteristics associated with the profile of cognitive deficits?
  7. Are there rehabilitation approaches that improve cognitive performance after stroke?
  8. Conclusion
  9. Acknowledgements
  10. References

General patterns can be detected in the profile of cognitive impairment after stroke: focal disorders such as aphasia and neglect are common, as are more diffuse abnormalities such as slowed information processing and executive dysfunction. Lesion mapping studies have been helpful in delineating the brain areas that contribute to domain-specific cognitive processes, and new research into how structural damage affects functional networks will further increase our understanding. Determining the causes of diffusely represented cognitive deficits is difficult but may well be related to sub-clinical vascular changes and subtle abnormalities in white matter; such factors are starting to be revealed by new imaging techniques. Cognitive rehabilitation approaches have been relatively successful for focal cortical deficits but less so for more generalized cognitive impairment. Repetitive transcranial magnetic stimulation and prism adaptation are two very different techniques to manipulate neural activity and drive plasticity. Further studies are needed to test other ways of stimulating functional brain changes after stroke to improve cognition.

Acknowledgements

  1. Top of page
  2. Abstract
  3. Introduction
  4. Defining cognitive impairment
  5. Is there a distinct profile of cognitive impairment arising from stroke?
  6. Are stroke characteristics associated with the profile of cognitive deficits?
  7. Are there rehabilitation approaches that improve cognitive performance after stroke?
  8. Conclusion
  9. Acknowledgements
  10. References

We thank Dr Jennifer Bradshaw for her valuable contribution to the section on neuropsychological assessment. Dr Cumming is funded by a National Heart Foundation Postdoctoral Research Fellowship. The Florey Neuroscience Institutes acknowledges strong support from the Victorian Government and in particular the funding from the Operational Infrastructure Support Grant.

References

  1. Top of page
  2. Abstract
  3. Introduction
  4. Defining cognitive impairment
  5. Is there a distinct profile of cognitive impairment arising from stroke?
  6. Are stroke characteristics associated with the profile of cognitive deficits?
  7. Are there rehabilitation approaches that improve cognitive performance after stroke?
  8. Conclusion
  9. Acknowledgements
  10. References
  • 1
    Feldman H, Levy AR, Hsiung GY et al. A Canadian cohort study of cognitive impairment and related dementias (ACCORD): study methods and baseline results. Neuroepidemiology 2003; 22:265274.
  • 2
    Hachinski V, Iadecola C, Petersen RC et al. National Institute of Neurological Disorders and Stroke-Canadian Stroke Network vascular cognitive impairment harmonization standards. Stroke 2006; 37:22202241.
  • 3
    Tatemichi TK, Desmond DW, Stern Y, Paik M, Sano M, Bagiella E. Cognitive impairment after stroke: frequency, patterns, and relationship to functional abilities. J Neurol Neurosurg Psychiatry 1994; 57:202207.
  • 4
    Hochstenbach J, Mulder T, van Limbeek J, Donders R, Schoonderwaldt H. Cognitive decline following stroke: a comprehensive study of cognitive decline following stroke. J Clin Exp Neuropsychol 1998; 20:503517.
  • 5
    Srikanth VK, Thrift AG, Saling MM et al. Increased risk of cognitive impairment 3 months after mild to moderate first-ever stroke: a community-based prospective study of nonaphasic English-speaking survivors. Stroke 2003; 34:11361143.
  • 6
    Sachdev PS, Brodaty H, Valenzuela MJ et al. The neuropsychological profile of vascular cognitive impairment in stroke and TIA patients. Neurology 2004; 62:912919.
  • 7
    Knopman DS, Roberts RO, Geda YE et al. Association of prior stroke with cognitive function and cognitive impairment. Arch Neurol 2009; 66:614619.
  • 8
    Schneider JA, Wilson RS, Cochran EJ et al. Relation of cerebral infarctions to dementia and cognitive function in older persons. Neurology 2003; 60:10821088.
  • 9
    Jokinen H, Gouw AA, Madureira S et al. Incident lacunes influence cognitive decline. Neurology 2011; 76:18721878.
  • 10
    Rasquin S, Lodder J, Verhey F. The association between psychiatric and cognitive symptoms after stroke: a prospective study. Cerebrovasc Dis 2005; 19:309316.
  • 11
    Barker-Collo S, Feigin VL, Parag V, Lawes CM, Senior H. Auckland Stroke Outcomes Study. Part 2: cognition and functional outcomes 5 years poststroke. Neurology 2010; 75:16081616.
  • 12
    Narasimhalu K, Ang S, De Silva DA et al. The prognostic effects of poststroke cognitive impairment no dementia and domain-specific cognitive impairments in nondisabled ischemic stroke patients. Stroke 2011; 42:883888.
  • 13
    Nys GM, van Zandvoort MJ, de Kort PL, Jansen BP, de Haan EH, Kappelle LJ. Cognitive disorders in acute stroke: prevalence and clinical determinants. Cerebrovasc Dis 2007; 23:408416.
  • 14
    Lesniak M, Bak T, Czepiel W, Seniow J, Czlonkowska A. Frequency and prognostic value of cognitive disorders in stroke patients. Dement Geriatr Cogn Disord 2008; 26:356363.
  • 15
    Ballard C, Stephens S, Kenny R, Kalaria R, Tovee M, O'Brien J. Profile of neuropsychological deficits in older stroke survivors without dementia. Dement Geriatr Cogn Disord 2003; 16:5256.
  • 16
    Looi JC, Sachdev PS. Differentiation of vascular dementia from AD on neuropsychological tests. Neurology 1999; 53:670678.
  • 17
    Reed BR, Mungas DM, Kramer JH et al. Profiles of neuropsychological impairment in autopsy-defined Alzheimer's disease and cerebrovascular disease. Brain 2007; 130:731739.
  • 18
    Ingles JL, Wentzel C, Fisk JD, Rockwood K. Neuropsychological predictors of incident dementia in patients with vascular cognitive impairment, without dementia. Stroke 2002; 33:19992002.
  • 19
    Schneider JA, Boyle PA, Arvanitakis Z, Bienias JL, Bennett DA. Subcortical infarcts, Alzheimer's disease pathology, and memory function in older persons. Ann Neurol 2007; 62:5966.
  • 20
    Jaillard A, Grand S, Le Bas JF, Hommel M. Predicting cognitive dysfunctioning in nondemented patients early after stroke. Cerebrovasc Dis 2010; 29:415423.
  • 21
    Hoffmann M. Higher cortical function deficits after stroke: an analysis of 1,000 patients from a dedicated cognitive stroke registry. Neurorehabil Neural Repair 2001; 15:113127.
  • 22
    Pendlebury ST, Rothwell PM. Prevalence, incidence, and factors associated with pre-stroke and post-stroke dementia: a systematic review and meta-analysis. Lancet Neurol 2009; 8:10061018.
  • 23
    Srikanth VK, Quinn SJ, Donnan GA, Saling MM, Thrift AG. Long-term cognitive transitions, rates of cognitive change, and predictors of incident dementia in a population-based first-ever stroke cohort. Stroke 2006; 37:24792483.
  • 24
    Nys GM, Van Zandvoort MJ, De Kort PL et al. Domain-specific cognitive recovery after first-ever stroke: a follow-up study of 111 cases. J Int Neuropsychol Soc 2005; 11:795806.
  • 25
    Lazar RM, Minzer B, Antoniello D, Festa JR, Krakauer JW, Marshall RS. Improvement in aphasia scores after stroke is well predicted by initial severity. Stroke 2010; 41:14851488.
  • 26
    Lazar RM, Antoniello D. Variability in recovery from aphasia. Curr Neurol Neurosci Rep 2008; 8:497502.
  • 27
    Hochstenbach JB, den Otter R, Mulder TW. Cognitive recovery after stroke: a 2-year follow-up. Arch Phys Med Rehabil 2003; 84:14991504.
  • 28
    Desmond DW, Moroney JT, Sano M, Stern Y. Recovery of cognitive function after stroke. Stroke 1996; 27:17981803.
  • 29
    Gottesman RF, Hillis AE. Predictors and assessment of cognitive dysfunction resulting from ischaemic stroke. Lancet Neurol 2010; 9:895905.
  • 30
    Hillis AE. Aphasia: progress in the last quarter of a century. Neurology 2007; 69:200213.
  • 31
    Verdon V, Schwartz S, Lovblad KO, Hauert CA, Vuilleumier P. Neuroanatomy of hemispatial neglect and its functional components: a study using voxel-based lesion-symptom mapping. Brain 2010; 133(Pt 3):880894.
  • 32
    Vataja R, Pohjasvaara T, Mantyla R et al. MRI correlates of executive dysfunction in patients with ischaemic stroke. Eur J Neurol 2003; 10:625631.
  • 33
    Fassbender C, Murphy K, Foxe JJ et al. A topography of executive functions and their interactions revealed by functional magnetic resonance imaging. Brain Res Cogn Brain Res 2004; 20:132143.
  • 34
    Corbetta M, Shulman GL. Spatial neglect and attention networks. Annu Rev Neurosci 2011; 34:569599.
  • 35
    de Haan EH, Nys GM, Van Zandvoort MJ. Cognitive function following stroke and vascular cognitive impairment. Curr Opin Neurol 2006; 19:559564.
  • 36
    Tatemichi TK, Desmond DW, Prohovnik I. Strategic infarcts in vascular dementia. A clinical and brain imaging experience. Arzneimittelforschung 1995; 45:371385.
  • 37
    Pantoni L. Cerebral small vessel disease: from pathogenesis and clinical characteristics to therapeutic challenges. Lancet Neurol 2010; 9:689701.
  • 38
    Dufouil C, Godin O, Chalmers J et al. Severe cerebral white matter hyperintensities predict severe cognitive decline in patients with cerebrovascular disease history. Stroke 2009; 40:22192221.
  • 39
    Rasquin SM, Verhey FR, Lousberg R, Lodder J. Cognitive performance after first ever stroke related to progression of vascular brain damage: a 2 year follow up CT scan study. J Neurol Neurosurg Psychiatry 2005; 76:10751079.
  • 40
    Burton E, Ballard C, Stephens S et al. Hyperintensities and fronto-subcortical atrophy on MRI are substrates of mild cognitive deficits after stroke. Dement Geriatr Cogn Disord 2003; 16:113118.
  • 41
    Jokinen H, Kalska H, Mantyla R et al. White matter hyperintensities as a predictor of neuropsychological deficits post-stroke. J Neurol Neurosurg Psychiatry 2005; 76:12291233.
  • 42
    Medina D, DeToledo-Morrell L, Urresta F et al. White matter changes in mild cognitive impairment and AD: a diffusion tensor imaging study. Neurobiol Aging 2006; 27:663672.
  • 43
    Williamson J, Nyenhuis D, Stebbins GT et al. Regional differences in relationships between apparent white matter integrity, cognition and mood in patients with ischemic stroke. J Clin Exp Neuropsychol 2010; 32:673681.
  • 44
    Hillis AE, Wityk RJ, Barker PB et al. Subcortical aphasia and neglect in acute stroke: the role of cortical hypoperfusion. Brain 2002; 125(Pt 5):10941104.
  • 45
    Pantoni L, Garcia JH. Pathogenesis of leukoaraiosis: a review. Stroke 1997; 28:652659.
  • 46
    Marshall RS, Lazar RM. Pumps, aqueducts, and drought management: vascular physiology in vascular cognitive impairment. Stroke 2011; 42:221226.
  • 47
    Marshall RS, Festa JR, Cheung YK et al. Cerebral hemodynamics and cognitive impairment: baseline data from the RECON trial. Neurology 2012; 78:250255.
  • 48
    Stebbins GT, Nyenhuis DL, Wang C et al. Gray matter atrophy in patients with ischemic stroke with cognitive impairment. Stroke 2008; 39:785793.
  • 49
    Vogels RL, Oosterman JM, Laman DM et al. Transcranial Doppler blood flow assessment in patients with mild heart failure: correlates with neuroimaging and cognitive performance. Congest Heart Fail 2008; 14:6165.
  • 50
    Festa JR, Jia X, Cheung K et al. Association of low ejection fraction with impaired verbal memory in older patients with heart failure. Arch Neurol 2011; 68:10211026.
  • 51
    Almeida OP, Garrido GJ, Beer C, Lautenschlager NT, Arnolda L, Flicker L. Cognitive and brain changes associated with ischaemic heart disease and heart failure. Eur Heart J 2012; 33:17691776.
  • 52
    Frank B, Maschke M, Groetschel H et al. Aphasia and neglect are uncommon in cerebellar disease: negative findings in a prospective study in acute cerebellar stroke. Cerebellum 2010; 9:556566.
  • 53
    O'Halloran CJ, Kinsella GJ, Storey E. The cerebellum and neuropsychological functioning: a critical review. J Clin Exp Neuropsychol 2012; 34:3556.
  • 54
    Molinari M, Petrosini L, Misciagna S, Leggio MG. Visuospatial abilities in cerebellar disorders. J Neurol Neurosurg Psychiatry 2004; 75:235240.
  • 55
    Ravizza SM, McCormick CA, Schlerf JE, Justus T, Ivry RB, Fiez JA. Cerebellar damage produces selective deficits in verbal working memory. Brain 2006; 129(Pt 2):306320.
  • 56
    Schmahmann JD, Sherman JC. The cerebellar cognitive affective syndrome. Brain 1998; 121(Pt 4):561579.
  • 57
    Lagarde J, Hantkie O, Hajjioui A, Yelnik A. Neuropsychological disorders induced by cerebellar damage. Ann Phys Rehabil Med 2009; 52:360370.
  • 58
    Hochstenbach J, van Spaendonck KP, Cools AR, Horstink MW, Mulder T. Cognitive deficits following stroke in the basal ganglia. Clin Rehabil 1998; 12:514520.
  • 59
    Van der Werf YD, Scheltens P, Lindeboom J, Witter MP, Uylings HBM, Jolles J. Deficits of memory, executive functioning and attention following infarction in the thalamus: a study of 22 cases with localised lesions. Neuropsychologia 2003; 41:13301344.
  • 60
    Szirmai I, Vastagh I, Szombathelyi E, Kamondi A. Strategic infarcts of the thalamus in vascular dementia. J Neurol Sci 2002; 204:9197.
  • 61
    Williamson JD, Miller ME, Bryan RN et al. The Action to Control Cardiovascular Risk in Diabetes Memory in Diabetes Study (ACCORD-MIND): rationale, design, and methods. Am J Cardiol 2007; 99:112i122.
  • 62
    Hillis AE, Barker PB, Beauchamp NJ, Gordon B, Wityk RJ. MR perfusion imaging reveals regions of hypoperfusion associated with aphasia and neglect. Neurology 2000; 55:782788.
  • 63
    Tatemichi TK, Paik M, Bagiella E, Desmond DW, Pirro M, Hanzawa LK. Dementia after stroke is a predictor of long-term survival. Stroke 1994; 25:19151919.
  • 64
    Pasquini M, Leys D, Rousseaux M, Pasquier F, Henon H. Influence of cognitive impairment on the institutionalisation rate 3 years after a stroke. J Neurol Neurosurg Psychiatry 2007; 78:5659.
  • 65
    Claesson L, Linden T, Skoog I, Blomstrand C. Cognitive impairment after stroke – impact on activities of daily living and costs of care for elderly people. The Goteborg 70+ Stroke Study. Cerebrovasc Dis 2005; 19:102109.
  • 66
    Heruti RJ, Lusky A, Dankner R et al. Rehabilitation outcome of elderly patients after a first stroke: effect of cognitive status at admission on the functional outcome. Arch Phys Med Rehabil 2002; 83:742749.
  • 67
    Skidmore ER, Whyte EM, Holm MB et al. Cognitive and affective predictors of rehabilitation participation after stroke. Arch Phys Med Rehabil 2010; 91:203207.
  • 68
    Ryan JD, Polatajko HJ, McEwen S et al. Analysis of Cognitive Environmental Support (ACES): preliminary testing. Neuropsychol Rehabil 2011; 21:401427.
  • 69
    Wilson BA, Emslie HC, Quirk K, Evans JJ. Reducing everyday memory and planning problems by means of a paging system: a randomised control crossover study. J Neurol Neurosurg Psychiatry 2001; 70:477482.
  • 70
    Fish J, Manly T, Emslie H, Evans JJ, Wilson BA. Compensatory strategies for acquired disorders of memory and planning: differential effects of a paging system for patients with brain injury of traumatic versus cerebrovascular aetiology. J Neurol Neurosurg Psychiatry 2008; 79:930935.
  • 71
    Winkens I, Van Heugten CM, Wade DT, Habets EJ, Fasotti L. Efficacy of time pressure management in stroke patients with slowed information processing: a randomized controlled trial. Arch Phys Med Rehabil 2009; 90:16721679.
  • 72
    Cicerone KD, Dahlberg C, Malec JF et al. Evidence-based cognitive rehabilitation: updated review of the literature from 1998 through 2002. Arch Phys Med Rehabil 2005; 86:16811692.
  • 73
    Meinzer M, Rodriguez AD, Gonzalez Rothi LJ. First decade of research on constrained-induced treatment approaches for aphasia rehabilitation. Arch Phys Med Rehabil 2012; 93:S3545.
  • 74
    Naeser MA, Martin PI, Nicholas M et al. Improved picture naming in chronic aphasia after TMS to part of right Broca's area: an open-protocol study. Brain Lang 2005; 93:95105.
  • 75
    Barwood CH, Murdoch BE, Whelan BM et al. Improved language performance subsequent to low-frequency rTMS in patients with chronic non-fluent aphasia post-stroke. Eur J Neurol 2011; 18:935943.
  • 76
    Szaflarski JP, Vannest J, Wu SW, DiFrancesco MW, Banks C, Gilbert DL. Excitatory repetitive transcranial magnetic stimulation induces improvements in chronic post-stroke aphasia. Med Sci Monit 2011; 17:CR132139.
  • 77
    Rossetti Y, Rode G, Pisella L et al. Prism adaptation to a rightward optical deviation rehabilitates left hemispatial neglect. Nature 1998; 395:166169.
  • 78
    Shiraishi H, Yamakawa Y, Itou A, Muraki T, Asada T. Long-term effects of prism adaptation on chronic neglect after stroke. NeuroRehabilitation 2008; 23:137151.
  • 79
    Nys GM, de Haan EH, Kunneman A, de Kort PL, Dijkerman HC. Acute neglect rehabilitation using repetitive prism adaptation: a randomized placebo-controlled trial. Restor Neurol Neurosci 2008; 26:112.
  • 80
    das Nair RD, Lincoln NB. Cognitive rehabilitation for memory deficits following stroke. Cochrane Database Syst Rev 2007; (3):CD002293.
  • 81
    Lincoln NB, Majid MJ, Weyman N. Cognitive rehabilitation for attention deficits following stroke. Cochrane Database Syst Rev 2000; (4):CD002842.
  • 82
    Doornhein K, De Haan EHF. Cognitive training for memory deficits in stroke patients. Neuropsychol Rehabil 1998; 8:393400.
  • 83
    Sturm W, Willmes K. Efficacy of a reaction training on various attentional and cognitive functions in stroke patients. Neuropsychol Rehabil 1991; 1:259280.
  • 84
    Barker-Collo SL, Feigin VL, Lawes CM, Parag V, Senior H, Rodgers A. Reducing attention deficits after stroke using attention process training: a randomized controlled trial. Stroke 2009; 40:32933298.
  • 85
    Tzourio C, Anderson C, Chapman N et al. Effects of blood pressure lowering with perindopril and indapamide therapy on dementia and cognitive decline in patients with cerebrovascular disease. Arch Intern Med 2003; 163:10691075.
  • 86
    Diener HC, Sacco RL, Yusuf S et al. Effects of aspirin plus extended-release dipyridamole versus clopidogrel and telmisartan on disability and cognitive function after recurrent stroke in patients with ischaemic stroke in the Prevention Regimen for Effectively Avoiding Second Strokes (PRoFESS) trial: a double-blind, active and placebo-controlled study. Lancet Neurol 2008; 7:875884.
  • 87
    Meyer JS, Judd BW, Tawaklna T, Rogers RL, Mortel KF. Improved cognition after control of risk factors for multi-infarct dementia. JAMA 1986; 256:22032209.
  • 88
    Hillis AE, Ulatowski JA, Barker PB et al. A pilot randomized trial of induced blood pressure elevation: effects on function and focal perfusion in acute and subacute stroke. Cerebrovasc Dis 2003; 16:236246.
  • 89
    Jorge RE, Acion L, Moser D, Adams HP Jr, Robinson RG. Escitalopram and enhancement of cognitive recovery following stroke. Arch Gen Psychiatry 2010; 67:187196.
  • 90
    Narasimhalu K, Effendy S, Sim CH et al. A randomized controlled trial of rivastigmine in patients with cognitive impairment no dementia because of cerebrovascular disease. Acta Neurol Scand 2010; 121:217224.
  • 91
    Heyn P, Abreu BC, Ottenbacher KJ. The effects of exercise training on elderly persons with cognitive impairment and dementia: a meta-analysis. Arch Phys Med Rehabil 2004; 85:16941704.
  • 92
    Lautenschlager NT, Cox KL, Flicker L et al. Effect of physical activity on cognitive function in older adults at risk for Alzheimer disease: a randomized trial. JAMA 2008; 300:10271037.
  • 93
    Prakash RS, Snook EM, Erickson KI et al. Cardiorespiratory fitness: a predictor of cortical plasticity in multiple sclerosis. Neuroimage 2007; 34:12381244.
  • 94
    Angevaren M, Aufdemkampe G, Verhaar HJ, Aleman A, Vanhees L. Physical activity and enhanced fitness to improve cognitive function in older people without known cognitive impairment. Cochrane Database Syst Rev 2008; (2):CD005381.
  • 95
    Colcombe S, Kramer AF. Fitness effects on the cognitive function of older adults: a meta-analytic study. Psychol Sci 2003; 14:125130.
    Direct Link:
  • 96
    Cumming TB, Tyedin K, Churilov L, Morris ME, Bernhardt J. The effect of physical activity on cognitive function after stroke: a systematic review. Int Psychogeriatr 2012; 24:557567.
  • 97
    Quaney BM, Boyd LA, McDowd JM et al. Aerobic exercise improves cognition and motor function poststroke. Neurorehabil Neural Repair 2009; 23:879885.
  • 98
    Janssen H, Bernhardt J, Collier JM et al. An enriched environment improves sensorimotor function post-ischemic stroke. Neurorehabil Neural Repair 2010; 24:802813.
  • 99
    Sarkamo T, Tervaniemi M, Laitinen S et al. Music listening enhances cognitive recovery and mood after middle cerebral artery stroke. Brain 2008; 131(Pt 3):866876.
  • 100
    Glei DA, Landau DA, Goldman N, Chuang YL, Rodriguez G, Weinstein M. Participating in social activities helps preserve cognitive function: an analysis of a longitudinal, population-based study of the elderly. Int J Epidemiol 2005; 34:864871.
  • 101
    Hakansson K, Rovio S, Helkala EL et al. Association between mid-life marital status and cognitive function in later life: population based cohort study. BMJ 2009; 339:b2462.