Neurol Sci (2014) 35:1513–1518 DOI 10.1007/s10072-014-1897-z
REVIEW ARTICLE
Cognitive reserve in stroke and traumatic brain injury patients Domenica Nunnari • Placido Bramanti Silvia Marino
•
Received: 16 January 2014 / Accepted: 16 July 2014 / Published online: 23 July 2014 Ó Springer-Verlag Italia 2014
Abstract Cognitive reserve (CR) is defined as the ability to cope with brain damage due to pre-existing cognitive processes or to the development of new compensatory processes. Existing research on CR is mostly based on the study of neurodegenerative disorders, such as Alzheimer’s disease. Recently, however, this construct has also been applied to other neurological conditions, including multiple sclerosis, Parkinson’s disease, epilepsy, stroke, and traumatic brain injury. The present review provides an overview of the studies that have investigated the influence of CR on neuropsychological outcome in stroke and traumatic brain injury patients. We performed a selective search on MEDLINE, CINAHL, and Web of Science Core Collection, using specific keywords including ‘‘cognitive reserve’’, ‘‘stroke’’, and ‘‘traumatic brain injury’’. The review is organized as follows: the first section focuses on works investigating the effect of CR on neuropsychological outcomes in post-stroke patients; the second section discusses studies which support the CR theory in traumatic brain injury. This review suggests that the study of CR in adult brain injury is still insufficient. Future research should investigate the role of other variables, like cognitive and social activities, as markers of CR in patients with brain injury, functional brain correlates of CR in brain activity, and the effect of CR on brain injury rehabilitative outcomes. D. Nunnari (&) P. Bramanti S. Marino Neurobioimaging Laboratory, IRCCS Centro Neurolesi ‘‘Bonino-Pulejo’’, S.S. 113 Via Palermo, C.da Casazza, Messina 98124, Italy e-mail: [email protected] S. Marino Department of Biomedical Sciences and Morphological and Functional Imaging, University of Messina, Messina, Italy
Keywords Cognitive reserve Stroke Traumatic brain injury Neuropsychological outcome Premorbid intelligence Education Leisure activities
Introduction The concept of ‘reserve’ arises from the need to explain the discrepancy between brain damage and clinical manifestations in neurodegenerative diseases: more than 25 % of elderly subjects without cognitive impairment in neuropsychological assessment have postmortem pathological criteria of Alzheimer’s disease [1]. This means that it exists a non-linear relationship between the severity of brain damage and the corresponding clinical symptoms. This ‘reserve’ is classified in two ways. ‘Brain reserve’ refers to individual differences in the amount of available neural substrate—such as the brain volume, and the number of neurons or synapses—that allow some people to respond better than others to neuronal damage (passivestructural model) [2]. On the other hand, the active model refers to ‘cognitive reserve’ (CR) as the ability in processing cognitive tasks, due to pre-existing cognitive or compensatory processes [3]. Within the concept of CR, we can distinguish neural reserve and neural compensation. According to the former, an individual whose brain networks are more efficient, more capable, and more flexible is better able to cope with brain damage. The neural compensation, instead, is the individual variability in the ability to compensate for the pathological brain destruction of standard networks. This compensation helps to maintain or improve cognitive performances. The level of education, the intelligence quotient (IQ), the occupation, and the participation in cognitively stimulating activities are considered indicators of CR [4].
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In this review, we are particularly interested in the studies which considered the influence of CR on neuropsychological outcome in stroke and traumatic brain injury (TBI) patients. In fact, stroke is the third leading cause of death, and the second cause of disability and dementia in adults older than 65 years of age worldwide [5]. Moreover, TBI is the leading cause of death and lifelong disability in young adults, the greatest number of TBIs occurring in people aged 15–24 [6]. These dramatic events have personal and socioeconomic repercussions and represent a serious public health problem. Our aim is to provide an overview of the literature on CR in stroke and TBI patients, to underline the importance of incorporating this aspect in the comprehension of so different cognitive outcomes. A more complete view of the patients’ needs may help clinicians to plan individual interventions.
Materials and methods Selective search of MEDLINE, life science journals and online books (Pubmed), CINAHL database, and Web of Science Core Collection database was performed using specific keywords. Different combinations of the following terms were used to select the articles: ‘‘cognitive reserve’’, ‘‘stroke’’, ‘‘traumatic brain injury’’, ‘‘penetrating head injury’’, ‘‘education’’, ‘‘premorbid intelligence’’, ‘‘leisure activities’’, ‘‘occupation’’, ‘‘cognitive decline’’. Overall, 362 articles in English language, retrieved by electronic search on Medline (1983–2013), CINAHL (1993–2013), and Web of Science (2003–2013) were reviewed for inclusion. Our target was original studies investigating the impact of CR on cognitive outcome in adult stroke and TBI patients. Therefore, we excluded the following from this selective review: the studies that have measured the impact of CR on aspects different from cognitive outcome (i.e., functional outcome, return to work, psychosocial outcome), the studies that considered the CR accumulated in the period following brain injury (i.e., by cognitive stimulation or occupational therapy), pediatric studies. We also included three studies [7–9] frequently cited by selected articles. According to the inclusion/exclusion criteria mentioned above, thirteen studies were included in the review.
Cognitive reserve in stroke Cognitive impairment in stroke patients occurs in near half of survivors [7]. These neuropsychological deficits, more likely involved in information processing speed and executive functioning, are important determinants of functional
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stroke outcomes [8, 9]. Recent studies examining cognitive outcomes after stroke reported very different neuropsychological profiles in relation to clinical and demographic factors of victims. In particular, patients with anterior stroke produced significantly worse scores on tasks requiring visual abstract reasoning, word finding, and processing speed, whereas patients with posterior stroke performed best on almost all tests [10]. The studies that included the measure of CR among the variables, potentially able to influence the cognitive recovery in stroke population, use the level of education as proxy for CR. A longitudinal study by Sachdev et al. [11] examined the predictors of cognitive change after stroke or transitory ischemic attack (TIA), in the progression of cognitive impairment over 1 year (at 3, 6, and 14 months). This work selected a sample of patients without a history of stroke or TIA and excluded the subjects who had a cerebrovascular event in the interval period. The study observed 88 patients with ischemic vascular lesions who showed a small, gradual cognitive decline (especially in verbal memory and visuoconstructive function), in absence of further cerebrovascular events. The authors used different variables as predictors of cognitive decline: education was found to be the only predictor of cognitive decline after stroke or TIA, being negatively correlated. Although CR was not associated with the incidence of new brain infarct, Elkins et al. [12] analyzed the role of education in the relationship between cognitive function and magnetic resonance imaging (MRI), which defined the entity of brain infarct. In this study, 3,622 participants received an evaluation of cognitive functions (Modified Mini Mental State Examination—3MS and Digit Symbol Substitution Test—DSST) and MRI examination. These participants were classified in four education levels: (1) high school dropouts, (2) high school graduates, (3) vocational school or some college education, and 4) college graduates or advanced degrees. On a follow-up MRI (3.2–7.5 years after the baseline MRI) 254 subjects presented a new brain infarct. Among these, the individuals with the lowest education level had a greater decline in 3MS score than those with the higher education level. Only three 4 other studies considered the influence of CR on vascular brain injury outcomes. A recent work analyzed the association among educational history, cognitive deficits, and long-term survival in stroke patients, independently of white matter lesions [13]. The sample was divided in three groups according to educational history: 0–6, 7–9, C10 years. The neuropsychological assessment (3 months after stroke) measured global cognitive function, executive function, memory, language, visuospatial, and constructional abilities. 395 ischemic stroke patients were also examined by MRI. The results showed that short educational history was associated with neuropsychological
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deficits, dementia, and poor long-term post-stroke survival (follow-up for up to 12 years). Another recent study by Zieren et al. [14] investigated the role of the CR in the cognitive deterioration due to vascular pathology. In particular, they divided 247 patients with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) into two groups: 117 subjects with B10 years of education and 130 subjects with [10 years of education. The subjects underwent neuropsychological assessment (processing speed, working memory, reasoning, visuospatial ability, executive function, and verbal memory tasks) and MRI to assess brain damage. The effect of CR was observed only in patients with low or moderate disease severity: subjects with higher education level showed better performance in processing speed than patients with lower education at the same disease stage. However, there were no significant differences when brain damage was severe. The association between vascular pathology and cognitive functions was thus postulated to be mediated by the educational level. Although the participation in leisure activities as CR factor has been overlooked by the studies described above, Verghese et al. examined the association of participation in cognitive and physical leisure activities, measured at baseline, with risk of vascular cognitive impairment (VCI) in four hundred older adults. Among them, 71 developed incident VCI at follow-up examinations. According to findings, participants with frequent cognitive engagement had a reduced risk of VCI compared to those with low levels of cognitive activities [15]. Finally, a study by Gonzalez-Fernandez et al. [16] considered the role of CR in aphasic stroke patients. To determine if the severity of language dysfunction was affected by the individual’s educational level, the authors assessed several language functions in 173 stroke patients. These subjects were tested within 24 h of symptom onset. Additionally, 62 hospitalized control subjects with a diagnosis of TIA were tested after the resolution of their symptoms. Increasing years of education resulted in decreased severity of post-stroke aphasia in tasks that involved access to written words. This indicates that education provides resilience in spite of injury when access to written word is available. For details see Table 1.
Cognitive reserve in TBI Traumatic brain injury can result in long-term or lifelong cognitive, behavioral, and emotional consequences. At all levels of TBI severity, attention, processing speed, episodic memory, and executive function are most commonly affected [17]. Since the most of TBI population is injured at a relatively young age, before having the opportunity to
1515 Table 1 Studies on cognitive reserve in Stroke References
Sample
CR indicators
Results
Sachdev et al. [11]
88 patients with cerebrovascular disease and 71 controls
Education
Education is a protective factor against cognitive decline after stroke or TIA
Elkins et al. [12]
254 patients with new cerebral infarct
Education
Stroke patients with lowest education level have greater cognitive decline than those with highest level
OjalaOksala et al. [13]
395 patients with mild/moderate ischemic stroke
Education
Longer educational history is associated with smaller cognitive deficits, dementia, and favorable poststroke survival
Zieren et al. [14]
247 patients with CADASIL
Education
Verghese et al. [15]
71 elderly with VCI and 330 controls
Leisure activities
Better educated patients have better cognitive performance than worse-educated patients at the same level of brain pathology High level of participation in cognitive leisure activities (but not physical) are associated with reduced risk of VCI in older adults
GonzalezFernandez et al. [16]
173 stroke patients and 62 hospitalized controls
Education
Participants with 12 or more years of education have reduced rate of errors in multiple (mostly written) language tasks
TIA transitory ischemic attack, CADASIL cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy, VCI vascular cognitive impairment
acquire higher education and fulfill their employment potential, the relevance of CR in TBI is necessarily more limited than in age-related diseases. Accordingly, clinical variables, like injury severity, trauma-related factors, and concurrent cognitive status, are crucial aspects in determining the insult impact in adult TBI survivors [18]. The investigation of CR in these young patients, however, may facilitate the development of effective rehabilitation programs that meet the specific needs of each patient.
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The works investigating CR in stroke examined only mainly the influence of education on cognitive outcomes, indeed, most studies on cognitive status after TBI, discussed in this review, considered premorbid IQ as a CR as well. These studies estimated premorbid IQ using tests investigating cognitive functions considered markers of crystallized intelligence, as vocabulary and general and specific knowledge, because these functions (unlike those related to fluid intelligence) hold up well with brain damage. Alternatively, preinjury intelligence scores were obtained through school or military archives. In a pioneering study, Grafman et al. [19] analyzed 263 cases of Vietnam War veterans with penetrating head injuries. They found that veterans with higher preinjury score on induction test (Armed Forces Qualification Test) had a better intellectual outcome and response to treatment. Most recently Kesler et al. [20] compared American College Testing Program score (or an equivalent released by schools to estimate premorbid IQ) with Wechsler Adult Intelligence Scale-Revised (WAIS-R) score post TBI in 25 patients. The sample was divided in two groups according to preinjury standardized test scores. It is important to note that the high IQ group had also higher education level. The results showed that a low educational level/IQ seems to predispose patients to a higher vulnerability to cognitive impairment following TBI (that is, to a greater change in IQ from pre- to postinjury). Similarly, a Korean study described the relationship between premorbid demographic factors and neurocognitive outcomes following TBI [21]. The sample (293 patients) was composed of three subgroups: mild, moderate, and severe TBI. Demographic variables comprised: age, gender, marital status, educational level, occupation, place of residence, and premorbid intelligence. Education level was binned in three categories: unschooled, from 1 to 6 years of school, from 7 to 9 years, above 10 years. The occupational status was classified as unemployed, unskilled laborer/farmer, clerical worker, and merchant. After analyzing the effect of both these demographic variables and clinical factors on postmorbid neurocognitive functions (intelligence and memory), the authors concluded that higher levels of education and younger age were good prognostic factors for recovery of intelligence and memory, with the exception of the severe TBI group. In the most recent study on this topic, Sumowski et al. [22] reinforced the finding regarding the role of education in changing the impact of TBI on cognitive status. The authors compared a 44 patients’ group and a 36 healthy controls’ group on the predictive capacity of age, sex, and education on cognitive status. A group by education interaction showed that patients with lower education performed worse than healthy controls even if this discrepancy was attenuated in TBI survivors with higher education.
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Green et al. [23] found different results in 75 patients with moderate to severe TBIs. They examined the influence of age, premorbid IQ, and years of education on cognitive outcomes during the 12 months following a TBI. The neuropsychological assessment, performed at 2, 5, and 12 months after TBI, comprised the cognitive domains mainly impaired in TBI: simple and complex speed of processing, memory, executive functions, and attention span. The North American Adult Reading Test (NAART) or the Wechsler Test of Adult Reading (WTAR) provided the preinjury IQ. The results suggest that only age moderates cognitive recovery trajectories. In particular, the recovery of simple and complex speed of processing was better in younger patients. Higher premorbid IQ had no effect on recovery trajectories but was associated with higher functioning of simple processing speed, memory, and untimed executive function. These results suggest that (1) years of education have no significant effects on cognitive recovery, (2) age is a moderator of cognitive recovery trajectories during 12 months postinjury, (3) premorbid IQ plays a ‘buffering’ role against poor cognitive outcome. Furthermore, higher premorbid intelligence presented as a protective factor against cognitive decline in Vietnam veterans even after 30 years of penetrating head injury [24]. Within a prospective follow-up study (Vietnam Head Injury Study-Phase III) Raymont and colleagues investigated the role of demographic variables (education and race), premorbid intelligence (AFQT), brain volume loss, lesion location, and genetic markers (such as APOe4 and the COMT gene) in longterm cognitive decline after over 30 years from head injury. They found that preinjury performance, as measured by AFQT, was the most important determinant of postinjury intelligence. Finally, Ropacki et al. [25] conducted a complex research considering the effects of premorbid history variables on CR in closed head injury. The sample of 26 subjects was divided into two groups based on positive and negative premorbid history in respect to the presence of alcoholism, drug abuse, psychiatric history, previous neurological insult, and negative premorbid history. To measure patients’ premorbid intellectual function, the authors used the Oklahoma premorbid intelligence estimate (OPIE) that includes demographic information, vocabulary, and picture completion WAIS-R subtests. A comprehensive neuropsychological evaluation provided the measure of actual cognitive functioning of the sample. Since the postinjury discrepancy between verbal IQ and performance IQ was greater in the subjects with positive premorbid history, the authors concluded that the CR of that group was decreased. This rendered subjects with positive premorbid history more vulnerable to cognitive decline after head injury, than subjects with negative premorbid history. For details see Table 2.
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Table 2 Studies on cognitive reserve in TBI References
Sample
CR indicators
Results
Grafman et al. [19]
263 military with penetrating head injury and 64 controls
Premorbid intelligence (with AFQT); education
Patients with better preinjury cognitive status have less pre- to postinjury performance difference
Kesler et al. [20]
25 subjects with TBI
Premorbid IQ (with ACT); education
Lower premorbid IQ/education level predisposes to greater cognitive decline postinjury
Jeon et al. [21]
293 patients with TBI
Premorbid intelligence (with K-WAIS); education; occupation
Higher education level is a good prognostic factor for recovery of neurocognitive functions
Sumowski et al. [22]
44 patients with TBI and 36 healthy controls
Education
Higher education attenuates the negative effects of TBI on cognitive status
Green et al. [23]
75 patients with TBI
Premorbid IQ (with NAART); education
Higher premorbid IQ (but not education) has a ‘‘buffer influence’’ on cognitive functioning
Raymont et al. [24]
199 military with penetrating head injury and 55 healthy controls
Premorbid intelligence (with AFQT); education
Higher preinjury intelligence is the most consistent protective factor against cognitive decline over a period of more than 30 years
Ropacki et al. [25]
26 subjects with closed head injury
Premorbid intelligence (with OPIE)
Negative premorbid history in closed head injury (alcoholism, drug abuse, etc.) influences cognitive outcome via decreased cognitive reserve
TBI traumatic brain injury, IQ intelligence quotient, AFQT Armed Forces Qualification Test, ACT American College Testing Program score, NAART North American Adult Reading Test, OPIE Oklahoma premorbid intelligence estimate, K-WAIS Korean Wechsler Intelligence Scale
Discussion To date, there is vast epidemiologic evidence that CR mediates brain damage and the clinical manifestation of disease. The concept of CR relies on the idea that there can be individual differences in how tasks are processed. These differences can allow some subjects to cope better than others with brain changes. In this review, we briefly discuss the existing neuropsychological evidence on the CR hypothesis. We focus on stroke and TBI patients since these are the most epidemiological acquired adult brain diseases. In stroke CR studies, long educational history seems to be associated with less poststroke cognitive deficits. According to this literature, low education and premorbid intelligence are important risk factors for vascular dementia [26]. In patients with TBI it was observed that CR is one of the factors which may determine the insult impact in adult TBI survivors. Low education and premorbid IQ were the only variables reflecting CR that increased the vulnerability to cognitive impairment after TBI [20, 22, 23]. To understand the interpretation of these data, it is important to remember that CR is a hypothetical construct operationalized through indirect measures. CR and intelligence are related but they are distinct. The research on CR in Alzheimer’s dementia allowed for exploration of the influence of demographic and autobiographical data reflecting CR. Occupational attainment, leisure activities, and complex mental pursuits can reduce cognitive decline [27].
The current literature on brain injury outcomes has used education, premorbid IQ and, more rarely, occupation as proxy indicators of CR (results are summarized in Tables 1, 2). However, to our knowledge, there is no study that considers the role of other variables, such as engagement in stimulating mental, physical, and social activities during the lifetime as marker of CR, in modulating the cognitive outcome in stroke or TBI patients. A standardized instrument to measure CR, which considers education, occupational attainment, and leisure activities simultaneously, could be a better proxy for investigating such a complex construct. Recently Nucci et al. [28] developed a standardized questionnaire to measure CR for the Italian population (CRIq). The CRIq provides a global index including three main sources of CR: education, working activity, and leisure time activities. This tool has already been used in studies with healthy adults and elderly subjects [29, 30]. In future research, it would be interesting to apply it also to the brain injury population’s study. The literature reviewed in this paper suggests that the study of CR in adult brain injury is an area open to fruitful future research. Functional brain correlates of CR in brain activity have been observed in normal aging, mild cognitive impairment, and Alzheimer’s disease, using fMRI during cognitive tasks [31]. Future research should investigate whether and how CR variables modulate the pattern of task-related brain activity in stroke and TBI patients. Finally, it would be interesting to investigate the effects of CR on brain injury rehabilitative outcomes. In fact, other studies should be performed about the importance of early intervention to manage cognitive changes in stroke and
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TBI, through both pharmacologic and rehabilitative approaches. Conflict of interest
16.
The authors report no conflicts of interest. 17.
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REVIEW ARTICLE
Cognitive reserve in stroke and traumatic brain injury patients Domenica Nunnari • Placido Bramanti Silvia Marino
•
Received: 16 January 2014 / Accepted: 16 July 2014 / Published online: 23 July 2014 Ó Springer-Verlag Italia 2014
Abstract Cognitive reserve (CR) is defined as the ability to cope with brain damage due to pre-existing cognitive processes or to the development of new compensatory processes. Existing research on CR is mostly based on the study of neurodegenerative disorders, such as Alzheimer’s disease. Recently, however, this construct has also been applied to other neurological conditions, including multiple sclerosis, Parkinson’s disease, epilepsy, stroke, and traumatic brain injury. The present review provides an overview of the studies that have investigated the influence of CR on neuropsychological outcome in stroke and traumatic brain injury patients. We performed a selective search on MEDLINE, CINAHL, and Web of Science Core Collection, using specific keywords including ‘‘cognitive reserve’’, ‘‘stroke’’, and ‘‘traumatic brain injury’’. The review is organized as follows: the first section focuses on works investigating the effect of CR on neuropsychological outcomes in post-stroke patients; the second section discusses studies which support the CR theory in traumatic brain injury. This review suggests that the study of CR in adult brain injury is still insufficient. Future research should investigate the role of other variables, like cognitive and social activities, as markers of CR in patients with brain injury, functional brain correlates of CR in brain activity, and the effect of CR on brain injury rehabilitative outcomes. D. Nunnari (&) P. Bramanti S. Marino Neurobioimaging Laboratory, IRCCS Centro Neurolesi ‘‘Bonino-Pulejo’’, S.S. 113 Via Palermo, C.da Casazza, Messina 98124, Italy e-mail: [email protected] S. Marino Department of Biomedical Sciences and Morphological and Functional Imaging, University of Messina, Messina, Italy
Keywords Cognitive reserve Stroke Traumatic brain injury Neuropsychological outcome Premorbid intelligence Education Leisure activities
Introduction The concept of ‘reserve’ arises from the need to explain the discrepancy between brain damage and clinical manifestations in neurodegenerative diseases: more than 25 % of elderly subjects without cognitive impairment in neuropsychological assessment have postmortem pathological criteria of Alzheimer’s disease [1]. This means that it exists a non-linear relationship between the severity of brain damage and the corresponding clinical symptoms. This ‘reserve’ is classified in two ways. ‘Brain reserve’ refers to individual differences in the amount of available neural substrate—such as the brain volume, and the number of neurons or synapses—that allow some people to respond better than others to neuronal damage (passivestructural model) [2]. On the other hand, the active model refers to ‘cognitive reserve’ (CR) as the ability in processing cognitive tasks, due to pre-existing cognitive or compensatory processes [3]. Within the concept of CR, we can distinguish neural reserve and neural compensation. According to the former, an individual whose brain networks are more efficient, more capable, and more flexible is better able to cope with brain damage. The neural compensation, instead, is the individual variability in the ability to compensate for the pathological brain destruction of standard networks. This compensation helps to maintain or improve cognitive performances. The level of education, the intelligence quotient (IQ), the occupation, and the participation in cognitively stimulating activities are considered indicators of CR [4].
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In this review, we are particularly interested in the studies which considered the influence of CR on neuropsychological outcome in stroke and traumatic brain injury (TBI) patients. In fact, stroke is the third leading cause of death, and the second cause of disability and dementia in adults older than 65 years of age worldwide [5]. Moreover, TBI is the leading cause of death and lifelong disability in young adults, the greatest number of TBIs occurring in people aged 15–24 [6]. These dramatic events have personal and socioeconomic repercussions and represent a serious public health problem. Our aim is to provide an overview of the literature on CR in stroke and TBI patients, to underline the importance of incorporating this aspect in the comprehension of so different cognitive outcomes. A more complete view of the patients’ needs may help clinicians to plan individual interventions.
Materials and methods Selective search of MEDLINE, life science journals and online books (Pubmed), CINAHL database, and Web of Science Core Collection database was performed using specific keywords. Different combinations of the following terms were used to select the articles: ‘‘cognitive reserve’’, ‘‘stroke’’, ‘‘traumatic brain injury’’, ‘‘penetrating head injury’’, ‘‘education’’, ‘‘premorbid intelligence’’, ‘‘leisure activities’’, ‘‘occupation’’, ‘‘cognitive decline’’. Overall, 362 articles in English language, retrieved by electronic search on Medline (1983–2013), CINAHL (1993–2013), and Web of Science (2003–2013) were reviewed for inclusion. Our target was original studies investigating the impact of CR on cognitive outcome in adult stroke and TBI patients. Therefore, we excluded the following from this selective review: the studies that have measured the impact of CR on aspects different from cognitive outcome (i.e., functional outcome, return to work, psychosocial outcome), the studies that considered the CR accumulated in the period following brain injury (i.e., by cognitive stimulation or occupational therapy), pediatric studies. We also included three studies [7–9] frequently cited by selected articles. According to the inclusion/exclusion criteria mentioned above, thirteen studies were included in the review.
Cognitive reserve in stroke Cognitive impairment in stroke patients occurs in near half of survivors [7]. These neuropsychological deficits, more likely involved in information processing speed and executive functioning, are important determinants of functional
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stroke outcomes [8, 9]. Recent studies examining cognitive outcomes after stroke reported very different neuropsychological profiles in relation to clinical and demographic factors of victims. In particular, patients with anterior stroke produced significantly worse scores on tasks requiring visual abstract reasoning, word finding, and processing speed, whereas patients with posterior stroke performed best on almost all tests [10]. The studies that included the measure of CR among the variables, potentially able to influence the cognitive recovery in stroke population, use the level of education as proxy for CR. A longitudinal study by Sachdev et al. [11] examined the predictors of cognitive change after stroke or transitory ischemic attack (TIA), in the progression of cognitive impairment over 1 year (at 3, 6, and 14 months). This work selected a sample of patients without a history of stroke or TIA and excluded the subjects who had a cerebrovascular event in the interval period. The study observed 88 patients with ischemic vascular lesions who showed a small, gradual cognitive decline (especially in verbal memory and visuoconstructive function), in absence of further cerebrovascular events. The authors used different variables as predictors of cognitive decline: education was found to be the only predictor of cognitive decline after stroke or TIA, being negatively correlated. Although CR was not associated with the incidence of new brain infarct, Elkins et al. [12] analyzed the role of education in the relationship between cognitive function and magnetic resonance imaging (MRI), which defined the entity of brain infarct. In this study, 3,622 participants received an evaluation of cognitive functions (Modified Mini Mental State Examination—3MS and Digit Symbol Substitution Test—DSST) and MRI examination. These participants were classified in four education levels: (1) high school dropouts, (2) high school graduates, (3) vocational school or some college education, and 4) college graduates or advanced degrees. On a follow-up MRI (3.2–7.5 years after the baseline MRI) 254 subjects presented a new brain infarct. Among these, the individuals with the lowest education level had a greater decline in 3MS score than those with the higher education level. Only three 4 other studies considered the influence of CR on vascular brain injury outcomes. A recent work analyzed the association among educational history, cognitive deficits, and long-term survival in stroke patients, independently of white matter lesions [13]. The sample was divided in three groups according to educational history: 0–6, 7–9, C10 years. The neuropsychological assessment (3 months after stroke) measured global cognitive function, executive function, memory, language, visuospatial, and constructional abilities. 395 ischemic stroke patients were also examined by MRI. The results showed that short educational history was associated with neuropsychological
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deficits, dementia, and poor long-term post-stroke survival (follow-up for up to 12 years). Another recent study by Zieren et al. [14] investigated the role of the CR in the cognitive deterioration due to vascular pathology. In particular, they divided 247 patients with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) into two groups: 117 subjects with B10 years of education and 130 subjects with [10 years of education. The subjects underwent neuropsychological assessment (processing speed, working memory, reasoning, visuospatial ability, executive function, and verbal memory tasks) and MRI to assess brain damage. The effect of CR was observed only in patients with low or moderate disease severity: subjects with higher education level showed better performance in processing speed than patients with lower education at the same disease stage. However, there were no significant differences when brain damage was severe. The association between vascular pathology and cognitive functions was thus postulated to be mediated by the educational level. Although the participation in leisure activities as CR factor has been overlooked by the studies described above, Verghese et al. examined the association of participation in cognitive and physical leisure activities, measured at baseline, with risk of vascular cognitive impairment (VCI) in four hundred older adults. Among them, 71 developed incident VCI at follow-up examinations. According to findings, participants with frequent cognitive engagement had a reduced risk of VCI compared to those with low levels of cognitive activities [15]. Finally, a study by Gonzalez-Fernandez et al. [16] considered the role of CR in aphasic stroke patients. To determine if the severity of language dysfunction was affected by the individual’s educational level, the authors assessed several language functions in 173 stroke patients. These subjects were tested within 24 h of symptom onset. Additionally, 62 hospitalized control subjects with a diagnosis of TIA were tested after the resolution of their symptoms. Increasing years of education resulted in decreased severity of post-stroke aphasia in tasks that involved access to written words. This indicates that education provides resilience in spite of injury when access to written word is available. For details see Table 1.
Cognitive reserve in TBI Traumatic brain injury can result in long-term or lifelong cognitive, behavioral, and emotional consequences. At all levels of TBI severity, attention, processing speed, episodic memory, and executive function are most commonly affected [17]. Since the most of TBI population is injured at a relatively young age, before having the opportunity to
1515 Table 1 Studies on cognitive reserve in Stroke References
Sample
CR indicators
Results
Sachdev et al. [11]
88 patients with cerebrovascular disease and 71 controls
Education
Education is a protective factor against cognitive decline after stroke or TIA
Elkins et al. [12]
254 patients with new cerebral infarct
Education
Stroke patients with lowest education level have greater cognitive decline than those with highest level
OjalaOksala et al. [13]
395 patients with mild/moderate ischemic stroke
Education
Longer educational history is associated with smaller cognitive deficits, dementia, and favorable poststroke survival
Zieren et al. [14]
247 patients with CADASIL
Education
Verghese et al. [15]
71 elderly with VCI and 330 controls
Leisure activities
Better educated patients have better cognitive performance than worse-educated patients at the same level of brain pathology High level of participation in cognitive leisure activities (but not physical) are associated with reduced risk of VCI in older adults
GonzalezFernandez et al. [16]
173 stroke patients and 62 hospitalized controls
Education
Participants with 12 or more years of education have reduced rate of errors in multiple (mostly written) language tasks
TIA transitory ischemic attack, CADASIL cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy, VCI vascular cognitive impairment
acquire higher education and fulfill their employment potential, the relevance of CR in TBI is necessarily more limited than in age-related diseases. Accordingly, clinical variables, like injury severity, trauma-related factors, and concurrent cognitive status, are crucial aspects in determining the insult impact in adult TBI survivors [18]. The investigation of CR in these young patients, however, may facilitate the development of effective rehabilitation programs that meet the specific needs of each patient.
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The works investigating CR in stroke examined only mainly the influence of education on cognitive outcomes, indeed, most studies on cognitive status after TBI, discussed in this review, considered premorbid IQ as a CR as well. These studies estimated premorbid IQ using tests investigating cognitive functions considered markers of crystallized intelligence, as vocabulary and general and specific knowledge, because these functions (unlike those related to fluid intelligence) hold up well with brain damage. Alternatively, preinjury intelligence scores were obtained through school or military archives. In a pioneering study, Grafman et al. [19] analyzed 263 cases of Vietnam War veterans with penetrating head injuries. They found that veterans with higher preinjury score on induction test (Armed Forces Qualification Test) had a better intellectual outcome and response to treatment. Most recently Kesler et al. [20] compared American College Testing Program score (or an equivalent released by schools to estimate premorbid IQ) with Wechsler Adult Intelligence Scale-Revised (WAIS-R) score post TBI in 25 patients. The sample was divided in two groups according to preinjury standardized test scores. It is important to note that the high IQ group had also higher education level. The results showed that a low educational level/IQ seems to predispose patients to a higher vulnerability to cognitive impairment following TBI (that is, to a greater change in IQ from pre- to postinjury). Similarly, a Korean study described the relationship between premorbid demographic factors and neurocognitive outcomes following TBI [21]. The sample (293 patients) was composed of three subgroups: mild, moderate, and severe TBI. Demographic variables comprised: age, gender, marital status, educational level, occupation, place of residence, and premorbid intelligence. Education level was binned in three categories: unschooled, from 1 to 6 years of school, from 7 to 9 years, above 10 years. The occupational status was classified as unemployed, unskilled laborer/farmer, clerical worker, and merchant. After analyzing the effect of both these demographic variables and clinical factors on postmorbid neurocognitive functions (intelligence and memory), the authors concluded that higher levels of education and younger age were good prognostic factors for recovery of intelligence and memory, with the exception of the severe TBI group. In the most recent study on this topic, Sumowski et al. [22] reinforced the finding regarding the role of education in changing the impact of TBI on cognitive status. The authors compared a 44 patients’ group and a 36 healthy controls’ group on the predictive capacity of age, sex, and education on cognitive status. A group by education interaction showed that patients with lower education performed worse than healthy controls even if this discrepancy was attenuated in TBI survivors with higher education.
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Green et al. [23] found different results in 75 patients with moderate to severe TBIs. They examined the influence of age, premorbid IQ, and years of education on cognitive outcomes during the 12 months following a TBI. The neuropsychological assessment, performed at 2, 5, and 12 months after TBI, comprised the cognitive domains mainly impaired in TBI: simple and complex speed of processing, memory, executive functions, and attention span. The North American Adult Reading Test (NAART) or the Wechsler Test of Adult Reading (WTAR) provided the preinjury IQ. The results suggest that only age moderates cognitive recovery trajectories. In particular, the recovery of simple and complex speed of processing was better in younger patients. Higher premorbid IQ had no effect on recovery trajectories but was associated with higher functioning of simple processing speed, memory, and untimed executive function. These results suggest that (1) years of education have no significant effects on cognitive recovery, (2) age is a moderator of cognitive recovery trajectories during 12 months postinjury, (3) premorbid IQ plays a ‘buffering’ role against poor cognitive outcome. Furthermore, higher premorbid intelligence presented as a protective factor against cognitive decline in Vietnam veterans even after 30 years of penetrating head injury [24]. Within a prospective follow-up study (Vietnam Head Injury Study-Phase III) Raymont and colleagues investigated the role of demographic variables (education and race), premorbid intelligence (AFQT), brain volume loss, lesion location, and genetic markers (such as APOe4 and the COMT gene) in longterm cognitive decline after over 30 years from head injury. They found that preinjury performance, as measured by AFQT, was the most important determinant of postinjury intelligence. Finally, Ropacki et al. [25] conducted a complex research considering the effects of premorbid history variables on CR in closed head injury. The sample of 26 subjects was divided into two groups based on positive and negative premorbid history in respect to the presence of alcoholism, drug abuse, psychiatric history, previous neurological insult, and negative premorbid history. To measure patients’ premorbid intellectual function, the authors used the Oklahoma premorbid intelligence estimate (OPIE) that includes demographic information, vocabulary, and picture completion WAIS-R subtests. A comprehensive neuropsychological evaluation provided the measure of actual cognitive functioning of the sample. Since the postinjury discrepancy between verbal IQ and performance IQ was greater in the subjects with positive premorbid history, the authors concluded that the CR of that group was decreased. This rendered subjects with positive premorbid history more vulnerable to cognitive decline after head injury, than subjects with negative premorbid history. For details see Table 2.
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Table 2 Studies on cognitive reserve in TBI References
Sample
CR indicators
Results
Grafman et al. [19]
263 military with penetrating head injury and 64 controls
Premorbid intelligence (with AFQT); education
Patients with better preinjury cognitive status have less pre- to postinjury performance difference
Kesler et al. [20]
25 subjects with TBI
Premorbid IQ (with ACT); education
Lower premorbid IQ/education level predisposes to greater cognitive decline postinjury
Jeon et al. [21]
293 patients with TBI
Premorbid intelligence (with K-WAIS); education; occupation
Higher education level is a good prognostic factor for recovery of neurocognitive functions
Sumowski et al. [22]
44 patients with TBI and 36 healthy controls
Education
Higher education attenuates the negative effects of TBI on cognitive status
Green et al. [23]
75 patients with TBI
Premorbid IQ (with NAART); education
Higher premorbid IQ (but not education) has a ‘‘buffer influence’’ on cognitive functioning
Raymont et al. [24]
199 military with penetrating head injury and 55 healthy controls
Premorbid intelligence (with AFQT); education
Higher preinjury intelligence is the most consistent protective factor against cognitive decline over a period of more than 30 years
Ropacki et al. [25]
26 subjects with closed head injury
Premorbid intelligence (with OPIE)
Negative premorbid history in closed head injury (alcoholism, drug abuse, etc.) influences cognitive outcome via decreased cognitive reserve
TBI traumatic brain injury, IQ intelligence quotient, AFQT Armed Forces Qualification Test, ACT American College Testing Program score, NAART North American Adult Reading Test, OPIE Oklahoma premorbid intelligence estimate, K-WAIS Korean Wechsler Intelligence Scale
Discussion To date, there is vast epidemiologic evidence that CR mediates brain damage and the clinical manifestation of disease. The concept of CR relies on the idea that there can be individual differences in how tasks are processed. These differences can allow some subjects to cope better than others with brain changes. In this review, we briefly discuss the existing neuropsychological evidence on the CR hypothesis. We focus on stroke and TBI patients since these are the most epidemiological acquired adult brain diseases. In stroke CR studies, long educational history seems to be associated with less poststroke cognitive deficits. According to this literature, low education and premorbid intelligence are important risk factors for vascular dementia [26]. In patients with TBI it was observed that CR is one of the factors which may determine the insult impact in adult TBI survivors. Low education and premorbid IQ were the only variables reflecting CR that increased the vulnerability to cognitive impairment after TBI [20, 22, 23]. To understand the interpretation of these data, it is important to remember that CR is a hypothetical construct operationalized through indirect measures. CR and intelligence are related but they are distinct. The research on CR in Alzheimer’s dementia allowed for exploration of the influence of demographic and autobiographical data reflecting CR. Occupational attainment, leisure activities, and complex mental pursuits can reduce cognitive decline [27].
The current literature on brain injury outcomes has used education, premorbid IQ and, more rarely, occupation as proxy indicators of CR (results are summarized in Tables 1, 2). However, to our knowledge, there is no study that considers the role of other variables, such as engagement in stimulating mental, physical, and social activities during the lifetime as marker of CR, in modulating the cognitive outcome in stroke or TBI patients. A standardized instrument to measure CR, which considers education, occupational attainment, and leisure activities simultaneously, could be a better proxy for investigating such a complex construct. Recently Nucci et al. [28] developed a standardized questionnaire to measure CR for the Italian population (CRIq). The CRIq provides a global index including three main sources of CR: education, working activity, and leisure time activities. This tool has already been used in studies with healthy adults and elderly subjects [29, 30]. In future research, it would be interesting to apply it also to the brain injury population’s study. The literature reviewed in this paper suggests that the study of CR in adult brain injury is an area open to fruitful future research. Functional brain correlates of CR in brain activity have been observed in normal aging, mild cognitive impairment, and Alzheimer’s disease, using fMRI during cognitive tasks [31]. Future research should investigate whether and how CR variables modulate the pattern of task-related brain activity in stroke and TBI patients. Finally, it would be interesting to investigate the effects of CR on brain injury rehabilitative outcomes. In fact, other studies should be performed about the importance of early intervention to manage cognitive changes in stroke and
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TBI, through both pharmacologic and rehabilitative approaches. Conflict of interest
16.
The authors report no conflicts of interest. 17.
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