Effect of Formal Education on Vascular Cognitive Impairment after Stroke: A Meta-analysis and Study in Young-Stroke Patients.

OBJECTIVES: The extent of vascular cognitive impairment (VCI) after stroke varies greatly across individuals, even when the same amount of brain damage is present. Education level is a potentially protective factor explaining these differences, but results on its effects on VCI are inconclusive. METHODS: First, we performed a meta-analysis on formal education and VCI, identifying 21 studies (N=7770). Second, we examined the effect of formal education on VCI in young-stroke patients who were cognitively assessed on average 11.0 (SD=8.2) years post-stroke (the FUTURE study cohort). The total sample consisted of 277 young-stroke patients with a mean age at follow-up 50.9 (SD=10.3). Age and education-adjusted expected scores were computed using 146 matched stroke-free controls. RESULTS: The meta-analysis showed an overall effect size (z') of 0.25 (95% confidence interval [0.18-0.31]), indicating that formal education level had a small to medium effect on VCI. Analyses of the FUTURE data showed that the effect of education on post-stroke executive dysfunction was mediated by age (ß age -0.015; p<.05). Below-average performance in the attention domain was more frequent for low-education patients (χ2(2)=9.8; p<.05). CONCLUSIONS: While education level was found to be related to post-stroke VCI in previous research, the effects were small. Further analysis in a large stroke cohort showed that these education effects were fully mediated by age, even in relatively young stroke patients. Education level in and of itself does not appear to be a valid indicator of cognitive reserve. Multi-indicator methods may be more valid, but have not been studied in relation to VCI. (JINS, 2017, 23, 223-238).

Remote Lower White Matter Integrity Increases the Risk of Long-Term Cognitive Impairment After Ischemic Stroke in Young Adults.

BACKGROUND AND PURPOSE: Poststroke cognitive impairment occurs frequently in young patients with ischemic stroke (18 through 50 years of age). Accumulating data suggest that stroke is associated with lower white matter integrity remote from the stroke impact area, which might explain why some patients have good long-term cognitive outcome and others do not. Given the life expectancy of decades in young patients, we therefore investigated remote white matter in relation to long-term cognitive function. METHODS: We included all consecutive first-ever ischemic stroke patients, left/right hemisphere, without recurrent stroke or transient ischemic attack during follow-up, aged 18 through 50 years, admitted to our university medical center between 1980 and 2010. One hundred seventeen patients underwent magnetic resonance imaging scanning including a T1-weighted scan, a diffusion tensor imaging scan, and completed a neuropsychological assessment. Patients were compared with a matched stroke-free control group (age, sex, and education matched). Cognitive impairment was defined as >1.5 SD below the mean cognitive index score of controls and no cognitive impairment as ≤1 SD. Tract-Based Spatial Statistics was used to assess the white matter integrity (fractional anisotropy and mean diffusivity). RESULTS: About 11 years after ischemic stroke, lower remote white matter integrity was associated with a worse long-term cognitive performance. A lower remote white matter integrity, even in the contralesional hemisphere, was observed in cognitively impaired patients (n=25) compared with cognitively unimpaired patients (n=71). CONCLUSIONS: These findings indicate that although stroke has an acute onset, it might have long lasting effects on remote white matter integrity and thereby increases the risk of long-term cognitive impairment.

Ipsilateral hippocampal atrophy is associated with long-term memory dysfunction after ischemic stroke in young adults.

Memory impairment after stroke in young adults is poorly understood. In elderly stroke survivors memory impairments and the concomitant loss of hippocampal volume are usually explained by coexisting neurodegenerative disease (e.g., amyloid pathology) in interaction with stroke. However, neurodegenerative disease, such as amyloid pathology, is generally absent at young age. Accumulating evidence suggests that infarction itself may cause secondary neurodegeneration in remote areas. Therefore, we investigated the relation between long-term memory performance and hippocampal volume in young patients with first-ever ischemic stroke. We studied all consecutive first-ever ischemic stroke patients, aged 18-50 years, admitted to our academic hospital center between 1980 and 2010. Episodic memory of 173 patients was assessed using the Rey Auditory Verbal Learning Test and the Rey Complex Figure and compared with 87 stroke-free controls. Hippocampal volume was determined using FSL-FIRST, with manual correction. On average 10 years after stroke, patients had smaller ipsilateral hippocampal volumes compared with controls after left-hemispheric stroke (5.4%) and right-hemispheric stroke (7.7%), with most apparent memory dysfunctioning after left-hemispheric stroke. A larger hemispheric stroke was associated with a smaller ipsilateral hippocampal volume (b=-0.003, P<0.0001). Longer follow-up duration was associated with smaller ipsilateral hippocampal volume after left-hemispheric stroke (b=-0.028 ml, P=0.002) and right-hemispheric stroke (b=-0.015 ml, P=0.03). Our results suggest that infarction is associated with remote injury to the hippocampus, which may lower or expedite the threshold for cognitive impairment or even dementia later in life.

Post-stroke fatigue and its association with poor functional outcome after stroke in young adults.

INTRODUCTION: Post-stroke fatigue negatively influences short-term functional outcome in older stroke survivors. In young adults, in the midst of their active working and family life, this influence may even be more pronounced. However, there are only few studies on this topic in young patients with stroke. Therefore, we investigated the long-term prevalence of post-stroke fatigue in patients with a young transient ischaemic attack (TIA) or ischaemic stroke and its association with functional outcome. METHODS: This study is part of a large cohort study among 511 stroke survivors with a first-ever TIA or ischaemic stroke, aged 18-50 years. After a mean follow-up of 9.8 (SD 8.4) years, we assessed the presence of fatigue with the fatigue subscale of the Checklist Individual Strength questionnaire and functional outcome. Prevalence of fatigue between young patients with stroke and 147 stroke-free sex-matched and age-matched controls was compared. OR's for poor functional outcome on modified Rankin Score (mRS>2) and Instrumental Activities of Daily Living (IADL<8) and cognitive performance were calculated using logistic regression analysis. RESULTS: Of the young patients with stroke, 41% experienced symptoms of fatigue, versus 18.4% in controls (p 0.0005). Fatigue was associated with a poor functional outcome, as assessed by the mRS (OR 4.0 (95% CI 1.6 to 9.6), IADL (OR 2.2 (95% CI 1.1 to 4.6), and impairment in speed of information processing (OR 2.2 (95% CI 1.3 to 3.9). CONCLUSIONS: Fatigue was very common in young stroke survivors and was associated with a poor functional outcome, even after almost a decade of follow-up.

Persistent cognitive impairment after transient ischemic attack.

BACKGROUND AND PURPOSE: By definition, the symptoms of a transient ischemic attack (TIA) subside completely within 24 hours. Imaging studies show signs of persistent ischemic tissue damage in a substantial amount of patients with TIA. Cerebral infarction can cause permanent cognitive impairment. Whether permanent cognitive impairment occurs after TIA is unclear, as is its profile. METHODS: Patients with TIA aged 45 to 65 years without prior stroke or dementia underwent comprehensive neuropsychological testing within 3 months. Z scores per cognitive domain were obtained, based on the mean of a control group within the same age range. Cognitive impairment was defined as a domain z score <-1.65. Patients underwent either computed tomography or MRI brain imaging. RESULTS: One hundred seven patients with TIA (63% women, mean age, 56.6 years) were included and compared with 81 controls (56% women, mean age, 52.9 years). Patients performed worse on all cognitive domains except episodic memory. Working memory (25%), attention (22%), and information processing speed (16%) were most frequently impaired and more often than in the control group (age- and sex-adjusted odds ratios, respectively, 22.5 [95% confidence interval, 2.9-174.3], 6.8 [1.9-24.3], 7.1 [1.5-32.5]). More than 35% of patients with TIA had impairment of ≥1 cognitive domain. Presence of silent brain infarcts was related to worse executive functioning but did not explain the whole relationship between TIA and cognitive impairment. CONCLUSIONS: More than a third of patients with TIA have impairment of ≥1 cognitive domain within 3 months after their TIA. The affected domains fit in the vascular cognitive impairment profile.

Long-term cognitive impairment after first-ever ischemic stroke in young adults.

BACKGROUND AND PURPOSE: Up to 14% of all ischemic strokes occur in young adults (<50 years). Poststroke cognitive performance is a decisive determinant of their quality of life. However, virtually no studies report on cognition after young stroke, especially not on the long term. This long-term perspective is important because young patients have a long life expectancy during which they start forming a family, have an active social life, and make decisive career moves. We aimed to evaluate the long-term cognitive outcome. METHODS: All consecutive patients between January 1, 1980, and November 1, 2010, with a first-ever young ischemic stroke were recruited for cognitive assessment, using a matched stroke-free population as a reference. Composite Z scores for 7 cognitive domains were calculated and the ANCOVA model was used (Bonferroni correction). A below average performance was defined as >1.0 SD below the age-adjusted mean of the controls and cognitive impairment as >1.5 SD. RESULTS: Two hundred seventy-seven patients and 146 matched controls completed cognitive assessment (mean follow-up, 11.0 years, SD, 8.2; age, 50.9 years, SD, 10.3). Long-term cognitive outcome after an ischemic stroke was worse in most cognitive domains compared with a nonstroke population. Up to 50% of the patients had a below average performance or cognitive impairment. Deficits in processing speed, working memory, and attention were most common. CONCLUSIONS: Even 11 years after ischemic stroke in young adults, a substantial proportion of patients must cope with permanent cognitive deficits. These results have implications for information given to patients and rehabilitation services.

Anti-epileptogenesis: Electrophysiology, diffusion tensor imaging and behavior in a genetic absence model.

The beneficial effects of chronic and early pharmacological treatment with ethosuximide on epileptogenesis were studied in a genetic absence epilepsy model comorbid for depression. It was also investigated whether there is a critical treatment period and treatment length. Cortical excitability in the form of electrical evoked potentials, but also to cortico-thalamo-cortical network activity (spike-wave discharges, SWD and afterdischarges), white matter changes representing extra cortico-thalamic functions and depressive-like behavior were investigated. WAG/Rij rats received either ethosuximide for 2 months (post natal months 2-3 or 4-5), or ethosuximide for 4 months (2-5) in their drinking water, while control rats drank plain water. EEG measurements were made during treatment, and 6 days and 2 months post treatment. Behavioral test were also done 6 days post treatment. DTI was performed ex vivo post treatment. SWD were suppressed during treatment, and 6 days and 2 months post treatment in the 4 month treated group, as well as the duration of AD elicited by cortical electrical stimulation 6 days post treatment. Increased fractional anisotropy in corpus callosum and internal capsula on DTI was found, an increased P8 evoked potential amplitude and a decreased immobility in the forced swim test. Shorter treatments with ETX had no large effects on any parameter. Chronic ETX has widespread effects not only within but also outside the circuitry in which SWD are initiated and generated, including preventing epileptogenesis and reducing depressive-like symptoms. The treatment of patients before symptom onset might prevent many of the adverse consequences of chronic epilepsy.

Functional brain connectivity in young adults with post-stroke epilepsy.

Approximately 1 in 10 young stroke patients (18-50 years) will develop post-stroke epilepsy, which is associated with cognitive impairment. While previous studies have shown altered brain connectivity in patients with epilepsy, little is however known about the changes in functional brain connectivity in young stroke patients with post-stroke epilepsy and their relationship with cognitive impairment. Therefore, we aimed to investigate whether young ischaemic stroke patients have altered functional networks and whether this alteration is related to cognitive impairment. We included 164 participants with a first-ever cerebral infarction at young age (18-50 years), along with 77 age- and sex-matched controls, from the Follow-Up of Transient Ischemic Attack and Stroke patients and Unelucidated Risk Factor Evaluation study. All participants underwent neuropsychological testing and resting-state functional MRI to generate functional connectivity networks. At follow-up (10.5 years after the index event), 23 participants developed post-stroke epilepsy. Graph theoretical analysis revealed functional network reorganization in participants with post-stroke epilepsy, in whom a weaker (i.e. network strength), less-integrated (i.e. global efficiency) and less-segregated (i.e. clustering coefficient and local efficiency) functional network was observed compared with the participants without post-stroke epilepsy group and the controls (P < 0.05). Regional analysis showed a trend towards decreased clustering coefficient, local efficiency and nodal efficiency in contralesional brain regions, including the caudal anterior cingulate cortex, posterior cingulate cortex, precuneus, superior frontal gyrus and insula in participants with post-stroke epilepsy compared with those without post-stroke epilepsy. Furthermore, participants with post-stroke epilepsy more often had impairment in the processing speed domain than the group without post-stroke epilepsy, in whom the network properties of the precuneus were positively associated with processing speed performance. Our findings suggest that post-stroke epilepsy is associated with functional reorganization of the brain network after stroke that is characterized by a weaker, less-integrated and less-segregated brain network in young ischaemic stroke patients compared with patients without post-stroke epilepsy. The contralesional brain regions, which are mostly considered as hub regions, might be particularly involved in the altered functional network and may contribute to cognitive impairment in post-stroke epilepsy patients. Overall, our findings provide additional evidence for a potential role of disrupted functional network as underlying pathophysiological mechanism for cognitive impairment in patients with post-stroke epilepsy.

Risk factors and prognosis of young stroke. The FUTURE study: a prospective cohort study. Study rationale and protocol.

BACKGROUND: Young stroke can have devastating consequences with respect to quality of life, the ability to work, plan or run a family, and participate in social life. Better insight into risk factors and the long-term prognosis is extremely important, especially in young stroke patients with a life expectancy of decades. To date, detailed information on risk factors and the long-term prognosis in young stroke patients, and more specific risk of mortality or recurrent vascular events, remains scarce. METHODS/DESIGN: The FUTURE study is a prospective cohort study on risk factors and prognosis of young ischemic and hemorrhagic stroke among 1006 patients, aged 18-50 years, included in our study database between 1-1-1980 and 1-11-2010. Follow-up visits at our research centre take place from the end of 2009 until the end of 2011. Control subjects will be recruited among the patients' spouses, relatives or social environment. Information on mortality and incident vascular events will be retrieved via structured questionnaires. In addition, participants are invited to the research centre to undergo an extensive sub study including MRI. DISCUSSION: The FUTURE study has the potential to make an important contribution to increase the knowledge on risk factors and long-term prognosis in young stroke patients. Our study differs from previous studies by having a maximal follow-up of more than 30 years, including not only TIA and ischemic stroke but also hemorrhagic stroke, the addition of healthy controls and prospectively collect data during an extensive follow-up visit. Completion of the FUTURE study may provide better information for treating physicians and patients with respect to the prognosis of young stroke.

Accelerated development of cerebral small vessel disease in young stroke patients.

OBJECTIVE: To study the long-term prevalence of small vessel disease after young stroke and to compare this to healthy controls. METHODS: This prospective cohort study comprises 337 patients with an ischemic stroke or TIA, aged 18-50 years, without a history of TIA or stroke. In addition, 90 age- and sex-matched controls were included. At follow-up, lacunes, microbleeds, and white matter hyperintensity (WMH) volume were assessed using MRI. To investigate the relation between risk factors and small vessel disease, logistic and linear regression were used. RESULTS: After mean follow-up of 9.9 (SD 8.1) years, 337 patients were included (227 with an ischemic stroke and 110 with a TIA). Mean age of patients was 49.8 years (SD 10.3) and 45.4% were men; for controls, mean age was 49.4 years (SD 11.9) and 45.6% were men. Compared with controls, patients more often had at least 1 lacune (24.0% vs 4.5%, p < 0.0001). In addition, they had a higher WMH volume (median 1.5 mL [interquartile range (IQR) 0.5-3.7] vs 0.4 mL [IQR 0.0-1.0], p < 0.001). Compared with controls, patients had the same volume WMHs on average 10-20 years earlier. In the patient group, age at stroke (ß = 0.03, 95% confidence interval [CI] 0.02-0.04) hypertension (ß = 0.22, 95% CI 0.04-0.39), and smoking (ß = 0.18, 95% CI 0.01-0.34) at baseline were associated with WMH volume. CONCLUSIONS: Patients with a young stroke have a higher burden of small vessel disease than controls adjusted for confounders. Cerebral aging seems accelerated by 10-20 years in these patients, which may suggest an increased vulnerability to vascular risk factors.

Cognitive performance and poor long-term functional outcome after young stroke.

OBJECTIVE: To investigate the influence of cognitive performance on long-term functional outcome after ischemic stroke (IS) in young adults aged 18 through 50 years (young IS). METHODS: This study is part of a prospective cohort study among 277 stroke survivors with a young IS admitted to our department between January 1, 1980, and November 1, 2010. Functional outcome was assessed during follow-up between 2009 and 2012 with the modified Rankin Scale (mRS) and Instrumental Activities of Daily Living scale (IADL). Extensive neuropsychological investigation was performed. Logistic regression was used to calculate odds ratios (ORs) for a poor functional outcome (mRS >2 or IADL <8) for the 7 cognitive domains adjudicated for confounders. Cognitive function (continuous) as well as cognitive impairment (dichotomous) were studied. RESULTS: Only decline in working memory (OR 0.3, 95% confidence interval [CI] 0.1-0.6) was associated with poor functional outcome on the mRS. Except for decline in processing speed (OR 0.5, 95% CI 0.3-0.8) and working memory (OR 0.4, 95% CI 0.2-0.7), no relation was found with poor functional outcome on IADL. Impairment in none of the individual cognitive domains was related to long-term functional outcome, although impairment in global cognitive function was related to a poor functional outcome on the IADL (OR 4.8, 95% CI 1.7-14.0). CONCLUSIONS: On average, 11 years after young IS there was no clear relationship between long-term cognitive deficits and long-term functional outcome or IADL, stressing the need for further prospective studies with further development of sensitive measures of functional prognosis.

Lower Ipsilateral Hippocampal Integrity after Ischemic Stroke in Young Adults: A Long-Term Follow-Up Study.

BACKGROUND AND PURPOSE: Memory impairment after stroke is poorly understood as stroke rarely occurs in the hippocampus. Previous studies have observed smaller ipsilateral hippocampal volumes after stroke compared with controls. Possibly, these findings on macroscopic level are not the first occurrence of structural damage and are preceded by microscopic changes that may already be associated with a worse memory function. We therefore examined the relationship between hippocampal integrity, volume, and memory performance long after first-ever ischemic stroke in young adults. METHODS: We included all consecutive first-ever ischemic stroke patients, without hippocampal strokes or recurrent stroke/TIA, aged 18-50 years, admitted to our academic hospital between 1980 and 2010. One hundred and forty-six patients underwent T1 MPRAGE, DTI scanning and completed the Rey Auditory Verbal Learning Test and were compared with 84 stroke-free controls. After manual correction of hippocampal automatic segmentation, we calculated mean hippocampal fractional anisotropy (FA) and diffusivity (MD). RESULTS: On average 10 years after ischemic stroke, lesion volume was associated with lower ipsilateral hippocampal integrity (p<0.05), independent of hippocampal volume. In patients with a normal ipsilateral hippocampal volume (volume is less than or equal to 1.5 SD below the mean volume of controls) significant differences in ipsilateral hippocampal MD were observed (p<0.0001). However, patients with a normal hippocampal volume and high hippocampal MD did not show a worse memory performance compared with patients with a normal volume and low hippocampal MD (p>0.05). CONCLUSIONS: Patients with average ipsilateral hippocampal volume could already have lower ipsilateral hippocampal integrity, although at present with no attendant worse memory performance compared with patients with high hippocampal integrity. Longitudinal studies are needed to investigate whether a low hippocampal integrity after stroke might lead to exacerbated memory decline with increasing age.

Ischaemic stroke in young adults: risk factors and long-term consequences.

Contrary to trends in most other diseases, the average age of ischaemic stroke onset is decreasing, owing to a rise in the incidence of stroke among 'young' individuals (under 50 years of age). This Review provides a critical overview of the risk factors and aetiology of young ischaemic stroke and addresses its long-term prognosis, including cardiovascular risk, functional outcome and psychosocial consequences. We highlight the diminishing role of 'rare' risk factors in the pathophysiology of young stroke in light of the rising prevalence of 'traditional' vascular risk factors in younger age groups. Long-term prognosis is of particular interest to young patients, because of their long life expectancy and major responsibilities during a demanding phase of life. The prognosis of young stroke is not as favourable as previously thought, with respect either to mortality or cardiovascular disease or to psychosocial consequences. Therefore, secondary stroke prevention is probably a life-long endeavour in most young stroke survivors. Due to under-representation of young patients in past trials, new randomized trials focusing on this age group are needed to confirm the benefits of long-term secondary preventive medication. The high prevalence of poor functional outcome and psychosocial problems warrants further study to optimize treatment and rehabilitation for these young patients.

Long-term increased risk of unemployment after young stroke: a long-term follow-up study.

OBJECTIVE: To investigate the prevalence, excess risk, and risk factors of unemployment in patients after a TIA, ischemic stroke, or intracerebral hemorrhage at ages 18 through 50 years, compared with nationwide controls. METHODS: We performed a hospital-based cohort study among 694 patients, aged 18-50 years, with a first-ever TIA, ischemic stroke, or intracerebral hemorrhage. After a mean follow-up duration of 8.1 (SD 7.7) years, we used logistic regression analysis to calculate odds ratio (OR) with 95% confidence interval (CI) for being unemployed as a young stroke patient, compared with the Dutch population of vocational age (n = 7,803,000), with subsequent assessment of risk factors of unemployment. RESULTS: Young stroke patients had a higher risk of being unemployed than their peers in the Dutch population: women OR 2.3 (1.8-2.9), men OR 3.2 (2.5-4.0). A higher NIH Stroke Scale score at admission (OR 1.1 [95% CI 1.0-1.1]) and a longer follow-up duration (middle tertile OR 2.8 [95% CI 1.7-4.7], upper tertile OR 3.4 [95% CI 1.9-6.1]) were associated with a higher risk of being unemployed. CONCLUSION: Young stroke patients had a 2-3 times higher risk of unemployment after 8 years of follow-up. Return-to-work programs should be developed, adjusted, and evaluated in order to diminish the negative effects that unemployment can have on patients' life satisfaction and to limit the socioeconomic consequences.

Subjective cognitive failures after stroke in young adults: prevalent but not related to cognitive impairment.

Few studies exist on subjective cognitive failures after a stroke in young adults (≤50 years) and their relation to objective cognitive performance is unknown. Therefore, we investigated the prevalence of subjective cognitive failures in patients with a stroke in young adulthood and their relation with objective cognitive impairment. This study is part of the "Follow-Up of Transient ischemic attack and stroke patients and Unelucidated Risk factor Evaluation"-study (FUTURE study), including patients, aged 18-50 years, admitted to our hospital between 1980 and 2010 with a first-ever TIA or ischemic stroke. The prevalence of subjective cognitive failures in patients was determined and compared with 146 age- and sex-matched stroke-free controls. The relation of subjective failures with objective cognitive performance was investigated with linear and logistic regression analysis. 160 patients with a TIA and 277 with an ischemic stroke were included. After a mean follow-up of 10.1 (SD 8.3) years, the prevalence of subjective memory failures was 86.4% and that of subjective executive failures was 67.4% in patients, versus 69.7% (p = 0.008) and 41.4% (p = 0.002) in controls. A weak association between subjective memory failures and objective immediate (beta -0.12, p = 0.011) and delayed memory performance (beta -0.13, p = 0.010) was observed in patients. Subjective cognitive failures are prevalent after stroke in young adults, but not strongly related to objective cognitive impairment. Therefore, extensive neuropsychological assessment is essential for determination of objective cognitive impairment. However, it is important that subjective cognitive failures are recognized as they may indicate underlying psychosocial problems.