Aging, Brain Disease, and Reserve: Implications for Delirium

Abstract

Cognitive and brain reserve are well studied in the context of age-associated cognitive impairment and dementia. However, there is a paucity of research that examines the role of cognitive or brain reserve in delirium. Indicators (or proxy measures) of cognitive or brain reserve (such as brain size, education, activities) pose challenges in the context of the long prodromal phase of Alzheimer’s disease but are diminished in the context of delirium, which is of acute onset. This article provides a review of original articles on cognitive and brain reserve across many conditions affecting the central nervous system, with a focus on delirium. We review current definitions of reserve. We identify indicators for reserve utilized in earlier studies, and discuss these indicators in the context of delirium. We highlight future research directions to move the field ahead. Reserve may be a potentially modifiable characteristic. Studying the role of reserve in delirium can advance prevention strategies for delirium and may advance knowledge of reserve and its role in aging and neuropsychiatric disease generally.

Brain and cognitive reserve concepts developed from observations that some individuals demonstrate less cognitive impairment than others with comparable brain injury or neuropathology.^1-4 Higher functioning individuals were postulated to possess a reserve factor that acted to delay or ameliorate the impairments of intellect and functioning accompanying neurodegenerative conditions. Most research on reserve is based on studies in chronic progressive disorders such as Alzheimer’s disease.^{4, 5} Extrapolating the concept of reserve to delirium, an acute confusional state, may allow us to elucidate fundamental aspects of reserve and provide a unique opportunity to advance the field.

Delirium (an acute decline of cognition and attention) represents a common and serious problem for older persons, particularly in the face of acute illness and hospitalization.⁶ Delirium occurs in up to 56% of older adults in general hospital populations, and is associated with an in-hospital mortality of up to 33%.⁶ Delirium in older persons is associated with substantial morbidity, functional decline, loss of independence, nursing home placement, and death.⁶ Hospital costs of delirium are estimated to be greater than $8 billion annually, and post-hospital costs related to rehabilitation, institutionalization, and home care are greater than $100 billion annually.⁷

Clinical experience and previous studies demonstrate that delirium susceptibility varies between individuals. Delirium is typically the manifestation of a complex interrelationship between a vulnerable patient, subjected to noxious insults or precipitating factors. Previous studies have elucidated vulnerability factors for delirium including factors such as frailty, cognitive impairment, vision or hearing impairment, and comorbidity.^{8, 9} Cognitive and brain reserve concepts represents important new conceptualizations to capture this vulnerability to delirium.¹⁰ The poor outcomes of delirium cut across all causes of delirium, and persist even when controlling or stratifying by underlying causes. Thus, the outcomes may be attributable to the presence of the delirium itself, and not simply to the underlying causes. This conclusion is further supported by evidence that delirium of all causes (and its associated adverse effects) is preventable through targeted multicomponent risk factor interventions.^11-13 Thus, to maximize clinical relevance, we have considered the full scope of delirium and its multifactorial nature in this paper, and not single causes in isolation.

Objective

The purpose of this article is to review the concept of reserve in aging and brain disease and to probe its specific application to delirium. Most previous work on cognitive and brain reserve has focused on dementia and brain injury. Applying the concept to delirium requires some extrapolation, although Barnett and colleagues have previously extended the concept to neuropsychiatric disease.¹⁴ Important questions are whether the same reserve indicators (proxy measures) identified in previous studies will apply to delirium, and how proposed working definitions of reserve need to be altered to fit application to delirium. We summarize proposed working definitions of reserve, review previous studies of reserve with emphasis on studies of delirium, and highlight key indicators of reserve. We discuss features of delirium that heighten its clinical importance for further development of the neurocognitive reserve concept.

A Working Definition of Reserve

The reserve concept, which is applicable to a broad array of clinical disorders,¹⁵ describes variability across persons in the relationship of pathologic changes with clinical expression of disease.^{4, 16} In his most recent review, Stern¹⁷ articulates two models of reserve pertaining to neurocognitive functioning: brain and cognitive. Brain reserve refers to structural aspects of the brain, and cognitive reserve relates to how cognitive tasks are initiated and coordinated, involving access to complex cognitive networks. Stern suggests cognitive reserve is implemented via two mechanisms: neural reserve and neural compensation. Neural reserve describes the efficiency, capacity, or flexibility of brain networks or cognitive paradigms that underlie task performance in the healthy brain. Neural compensation refers to the ability to function optimally when pathology disrupts standard processing networks. Brain reserve is conceptualized as a passive process and evokes a threshold model (a critical level of brain capacity, or brain reserve capacity) for the adequate performance of cognitive tasks in the presence of pathology or depletion. Cognitive reserve is conceptualized as an active process by which pathology or depletion are met with greater efficiencies in pre-existing cognitive processes (neural reserve) or the enlistment of alternative processes (neural compensation) to achieve cognitive tasks.¹⁷

Current thinking is that reserve is dynamic and modifiable over the life course,¹⁵ and as such fits within the larger concept of brain plasticity.¹⁸ This, taken with evidence that brain structure and function are inseparable and are reciprocal causal agents,^{15, 17} leads us to conclude that a clean separation between brain vs. cognitive or active vs. passive reserve is not an actual reflection of biology. Thus we will use a more general term for reserve -- neurocognitive reserve^{19, 20} -- when discussing our own ideas. We use brain or cognitive reserve qualifiers when referring to published works, following the use of these concepts (or terms) in the original citation. As addressed in our discussion, more important conceptual distinctions are needed among the causes, indicators, and behavioral or clinical manifestations of reserve to inform theory development and the articulation of testable hypotheses.

Cognitive Reserve in Neuropsychiatric Illness

Recently Barnett and colleagues¹⁴ described the potential role for cognitive reserve theory in psychiatric illness. High cognitive reserve may provide resilience to cognitive failure, and protect persons by enhancing control over aberrant thoughts. Barnett and colleagues cite evidence for this view noting that low intelligence, disrupted education, lower brain and intra-cranial size are associated with risk and/or long term outcomes of schizophrenia and depression.¹⁴ Barnett and colleagues do not consider the role of cognitive reserve in delirium. However, we note that there are several studies demonstrating relationships between mental illness, cognitive impairment, dementia and delirium. Depression has been found to impair cognition in patients with dementia and may predict earlier onset of age-related cognitive impairment.^{21, 22} Similarly, affective disorders and symptoms have been associated with the risk for delirium in hospitalized and post-surgical patients.^23-25

Indicators of Cognitive and Brain Reserve

A critical first step in studying neurocognitive reserve is to identify indicators that accurately measure and quantify the concepts. If reserve is broadly defined as a discrepancy between observed and expected functional impairment associated with a given degree of neuropathology, then operationalizing reserve requires measures of both performance and neuropathology. In vivo measures of neuropathology in Alzheimer’s disease, such as amyloid imaging, have only recently been identified and are not widely available.²⁶ Autopsy studies have been used to identify the burden of disease in dementia. However, the neuropathological basis of delirium is poorly understood, and validated measures of neuropathology do not exist. Without a measure of neuropathology, the presence and severity of disease are approximated with standardized clinical measures and diagnostic criteria, such as neuropsychological testing and functional measures. Barnett and colleagues point out that investigations of cognitive reserve in the context of neuropsychiatric disease in the absence of well-established pathological markers (e.g., as validated by tissue examination or other biomarker) using performance or severity markers as proxies for pathology is a limited approach.¹⁴

Many indicators of brain reserve have been proposed. Head size, intracranial volume, brain volume, synaptic density and other anthropometric measures are considered suitable indicators.⁵ Proposed indicators of cognitive reserve include experiential characteristics that may boost neural connections (physical activity) or build problem solving skills (education, occupational complexity, mentally stimulating activities, intelligence).^{5, 27} Less commonly, physical activity, cognitive or leisure activities, and socioeconomic status are reported. To better understand the application of cognitive and brain reserve indicators, we conducted a review of the medical literature.

Methods

Systematic Review of Indicators of Brain and Cognitive Reserve

We conducted two searches of the PubMed database, limiting to English language articles published from January, 1988 through November, 2008. For the first search, to identify indicators of cognitive and brain reserve, we used the terms “cognitive reserve”, “neural reserve” and “brain reserve”, which were combined with “education”, “occupation”, “intelligence (IQ)”, “leisure”, “physical activity”, “socioeconomic status”, “social network”, “delirium”, “dementia”, “Parkinson’s disease”, “human immunodeficiency virus (HIV)”, “cognitive decline”, traumatic brain injury”, or “risk factor”. For the second search, to examine neuroimaging in reserve, we used the terms “cognitive reserve”, “brain reserve” and “neural reserve” in combination with “imaging”, “magnetic resonance imaging (MRI)”, “single photon emission computed tomography (SPECT)”, or “positron emission tomography (PET)”. The bibliographies of all articles were hand-searched for any additional pertinent articles. For the systematic reviews, we included only original articles.

Results

Our first review yielded 67 original articles on reserve indicators, summarized in Table 1 (reference listing available on request). The conditions examined in these studies were as follows (number of articles in parentheses): Alzheimer’s disease or dementia (53), delirium (4), cognitive decline (3), human immunodeficiency virus infections (4), traumatic brain injury (2), and Parkinson’s disease (1). A wide variety of reserve indicators were considered across these 67 studies, see Table 1. For the vast majority of studies, indicators of low reserve were associated with an increased risk of dementia or cognitive decline. The major reserve indicators and their measurement are detailed below.

TABLE 1.

Review of Studies on Brain or Cognitive Reserve (N=67)^*

Low Reserve Indicator	No. studies examining	Direction of association of low reserve indicator with risk of dementia or cognitive decline (No. studies)
		Increased risk	Decreased risk	No effect on risk
Low educational attainment	35	32	2	1
Low occupational indicator (unemployed or job with low mental demand)	14	13	1	--
Low level of cognitive or leisure activities	14	13	1	--
Low level of physical activity	12	10	--	2
Low socioeconomic status	6	4	1	1
Low intelligence quotient (IQ)	4	4	--	--
Unmarried status	3	3	--	--
Poor social supports	2	2	--	--

^*Includes only indicators with 2 or more published studies. Complete reference citations for articles available on request.

Educational Attainment and Measures of Socioeconomic Status

Socioeconomic status (SES) has been represented by education, occupation, income, individually or in combination.²⁸ Among cognitive or brain reserve indicators, educational attainment is the most widely studied. The strong inverse association of educational attainment with risk for dementia has led some investigators to claim that education may be the most important protective factor for dementia.²⁹ Education may increase brain reserve by promoting synaptic growth,³ and/or may foster cognitive reserve by generating new cognitive strategies.⁵

Occupation is also an important reserve indicator. One review³⁰ found that “high” (contrasting managerial, technical and professional occupations with unskilled, semi-skilled, trade and clerical workers) occupational status was associated with a 50% reduction in dementia risk. It is not clear how occupation may operate in models of neurocognitive reserve. Occupation may be a reflection of underlying intelligence or academic aptitude,^{31, 32} and therefore would be an outcome sharing a cause with a more fundamental neurocognitive reserve indicator. On the other hand, greater occupational complexity might enhance cognitive skills development throughout the lifetime,³³ and in this view would be a cause of neurocognitive reserve. Income has been found to predict cognitive decline independent of level of education, although the mechanism has not been speculated to conform to notions of brain or cognitive reserve.³⁴

Intelligence

Several previous studies have used intelligence as a marker for reserve. Typically, literacy or vocabulary measures are used to assess pre-morbid IQ.³⁵ Satz argued that psychometric intelligence was a direct measure of brain reserve capacity.⁴ Other investigators interpret literacy and vocabulary measures as indicators of educational quality.³⁶ Few lifespan studies are available that show the prospective relationship between early life intelligence and late life cognitive outcomes, but Whalley and colleagues have demonstrated that mental ability at age 11 is associated with risk for late onset dementia.³⁷

Cognitive or Leisure Activities

In a previous meta-analysis, participation in mentally stimulating activities was the most robust brain reserve indicator relative to education, occupation, and premorbid IQ.³⁰ Summary measures of cognitive activities have been developed to capture lifetime mental activity as an indicator of cognitive reserve.^38-40 Wilson’s Cognitive Activities Scale⁴¹ measures the frequency of participation in activities across the lifespan, including activities such as reading, writing, attending concerts. Other similarly composed activity scales have been proposed (e.g., the Florida Cognitive Activities Scale³⁹ and the Lifetime Experiences Questionnaire⁴⁰). These measures have been used to show that older persons with greater lifetime participation in complex mental activities showed less hippocampal atrophy,⁴² diminished cognitive decline,³⁸ and lower risk of Alzheimer’s disease.⁴³

Physical Activity

At least nine previous studies use physical activity as a cognitive or brain reserve indicator or otherwise describe a protective effect for cognitive decline or dementia,^44-51 although results of clinical trials are equivocal.^{52, 53} Exercise may increase brain reserve by promoting healthy cardiovascular function and diminishing cerebrovascular disease burden.⁵⁴ Exercise slows the expression of AD-like pathology in mouse models.⁵⁵ Exercise also enhances brain health and function by priming molecular memory for the plasticity molecule brain-derived neurotrophic factor.⁵⁶ Physical exercise and activity represents an neurocognitive reserve factor with public health implications, since it is potentially modifiable and produces a wide ranging health benefits.

Social Support

Epidemiological^{57, 58} and clinicopathological⁵⁹ studies have suggested a potential role for social supports (e.g., network size, marital status) in dementia risk. The postulate is that cognitive processes that support the development and maintenance of social networks promote cognitive reserve.⁵⁹ Inouye found social support was related to delirium risk in a hospitalized cohort, but the effect was not independent of other predictors including cognitive level and medical comorbidity.⁹

Anthropometric Indicators

Head circumference is often used a proxy for brain size and brain reserve, and has been shown to mitigate risk for dementia in some,^60-62 but not all studies.⁶³ One previous study⁶⁰ demonstrated an interaction between head circumference and educational attainment in the risk for Alzheimer’s disease, implying that increases in risk for AD due to small head circumference can be overcome by high education.

Neuroimaging Indicators

Neuroimaging markers can be used as both proxy measures of cognitive or brain reserve or as measures of neuropathology. For the present study, we included only those studies that examined a cognitive or brain reserve indicator (such as education) in correlation with an imaging measure, and where the imaging was used to indicate the burden of neuropathology. Imaging studies that used the imaging modality itself as a proxy measure of brain or cognitive reserve were not included. We were unable to identify neuroimaging studies examining the role of reserve in delirium.

Our systematic review yielded 25 original articles in which cognitive or brain reserve indicators were correlated with imaging findings (Table 2, references available on request). The conditions examined in these studies were (number of studies in parentheses): Alzheimer’s disease (16), unspecified cognitive decline (3), mild cognitive impairment (4), frontotemporal dementia (2), and human immunodeficiency virus-related cognitive impairment (2). Cognitive or brain reserve indicators included education, intelligence (IQ), and occupational attainment, which were correlated with neuroimaging findings of increased brain pathology, including decreased brain volume, decreased cerebral blood flow, decreased metabolic activity, altered task-activation, increased amyloid uptake, and presence of white matter hyperintensities. For the majority of studies we identified, indicators of high cognitive reserve (such as education, occupation, and IQ) were correlated with a higher degree of brain pathology by neuroimaging for the same degree of functional impairment.

TABLE 2.

Correlation of Cognitive Reserve Indicators With Imaging Findings (N = 25)

Imaging Finding (Indicating Increased Neuropathology)	No. of Studies	Association of Imaging Finding With Reserve Markera (No. of Studies)
		High Reserve	Low Reserve	No Association
Decreased brain volumeb	5	3	–	2
Decreased cerebral blood flow	7	6	1	–
Decreased metabolic activity	6	6	–	–
Altered task activation	5	5	–	–
Increased PIB uptake	2	2	–	–
Presence of WMH	2	1	–	1

Notes: Complete reference citations available on request. For a given level of functioning, patients with reserve have more neuropathological findings. PIB: Pittsburgh Compound B; WMH: white matter hyperintensity.

^aReserve markers include education, IQ, and occupational attainment. A single study (Sole-Padulles C, Bartres-Faz D, Junqué C, et al. Brain structure and function related to cognitive reserve variables in normal aging, mild cognitive impairment and Alzheimer’s Disease. Neurobiol Aging 2009; 30:1114 – 1124) included multiple imaging modalities and contributed to both decreased brain volume and increased task activation.

^bDecreased brain volume includes increased ventricle size, presence of atrophy, or reduced intracranial volume.

Functional neuroimaging (including SPECT, PET, or fMRI) can measure resting blood flow or metabolic activity, or changes in blood flow or metabolic activity with task-related activation studies. Resting measures of blood flow or metabolic activity are important markers of neuropathology. Studies in AD patients have shown diminished cerebral blood flow in the parietotemporal regions in people with high vs. low education at comparable cognitive and functional level.⁶⁴ This pattern supports cognitive reserve theory.¹⁷ Persons with more neurocognitive reserve will be able to perform at a given level with greater neuropathology than persons with low reserve.

A study using the brain amyloid PET ligand 11C-labelled Pittsburgh Compound B (PIB) has demonstrated that education delays expression of clinical symptoms in the presence of markers of AD pathology.⁶⁵ After controlling for dementia severity and relative to patients with low education, patients with higher education had more amyloid binding in the ventrolateral frontal cortex and reduced metabolism in the temporal and parietal cortex.

Studies on Reserve in Delirium

Brain and cognitive reserve have not been widely studied in the context of delirium. Our comprehensive review identified two previous studies that identified educational attainment as an important predictor of delirium (with a moderate to large effect size),^{66, 67} but at least three failed to demonstrate a significant association.^68-70 We have examined the role of educational attainment and the risk for delirium in two large prospective cohorts.¹⁰ Briefly, the two studies involved cohorts of hospitalized elders who were at least 70 years and free from delirium ratings at hospital admission.⁷¹ In both cohorts, mean years of education among persons who developed delirium while hospitalized was 9 years, compared to 11 years among those who did not (P<.001), and the effect remained after control for possible confounders. The magnitude of difference was medium (d=.48 and .51, respectively). A five year difference in educational attainment was associated with a 1.6-fold decrease in the odds of delirium. Thus, education was strongly related to the risk of delirium.

In a related study⁷², we evaluated the same cohorts, but focused on the role that leisure activity participation prior to hospitalization played in mediating the protective influence of educational attainment on delirium. We also explored differential effects of specific activities on the risk for delirium. Frequency of participation was assessed in 10 specific types of activities: physical exercise; yard work; hobbies; entertainment activities; reading; working at a paid or volunteer job; regularly playing games; attending religious services; visiting friends; and participating in groups. Both education and activity significantly predicted lower risk for delirium, while controlling for sociodemographic characteristics and comorbidities. In addition, activity participation fully mediated the relationship of education and risk for delirium. After exploring specific activities, participation in regular physical exercise exerted the greatest protective effect against delirium.

Discussion

This article provides a review of original articles on general neurocognitive reserve across many conditions affecting the central nervous system. We have reviewed the current definitions of reserve, including both brain and cognitive reserve and have identified indicators for reserve used in earlier studies. Neurocognitive reserve may be promoted by socioeconomic status indicators such as educational attainment, as well as by cognitive and physical activities. In delirium, educational attainment and activity participation are important predictors of delirium. Activity level is potentially modifiable and can preserve cognitive functioning in later life, providing a target for preventive interventions.

Neurocognitive Reserve Indicators in Dementia and Delirium

Many studies use SES variables (education, occupation, income) as proxies for cognitive reserve. There are important challenges in using SES variables in aging research. Birth cohort effects, and sex and race/ethnicity differences in the average level of and quality of education⁷³ may be a source of bias.⁷⁴ Moreover, education may cause measurement bias in the assessment of neuropsychological performance.^{75, 76} Socioeconomic status and cultural background may confound the meaning of educational attainment,⁷⁴ or contribute to psychopathology via mechanisms not consistent with cognitive reserve theory.^{77, 78}

Recognizing limitations of SES indicators, some investigators have turned to measures of literacy or reading level to capture academic achievement.^{79, 80} Such measures are also often used as measures of intelligence or premorbid intelligence, also often used as indicators of brain reserve.^{30, 79} This strategy assumes performance on reading and literacy tests is resistant to the effects of brain pathology.⁸¹ However, estimates of pre-morbid IQ based on literacy tests are generally accurate in persons without dementia, but less accurate among persons with AD.⁸² It is reasonable to propose that accumulating neuropathology might limit vocabulary development, since AD- type neuropathological changes may be present decades prior to diagnosis (even as early as age 25⁸³) and vocabulary development peaks in middle age (ages 35-45⁸⁴). Therefore, the long preclinical phase of AD poses a challenge to studies of the existence and mechanism of neurocognitive reserve.

Problems inherent in the long preclinical phase of AD may also limit the utility of other indicators of neurocognitive reserve, such as engagement in mentally stimulating activity, and educational and occupational attainment.⁵ On the other hand, delirium is not associated with a long preclinical phase. Examining indicators of neurocognitive reserve in the context of delirium may offer substantive advantages and may provide insights into the fundamental role of neurocognitive reserve in neuropsychiatric illness.

The Importance of Measures of Neuropathology

If neurocognitive reserve is conceptualized as a discrepancy between observed and expected functional impairment associated with a given degree of neuropathology, studies of neurocognitive reserve requires measures of both performance and neuropathology. Clinicopathologic autopsy studies are not uncommon in Alzheimer’s disease (AD) and other dementias, and new imaging techniques offer the possibility of prospective studies of accumulating neuropathology in AD. Since he neuropathological basis of delirium is poorly understood, this is a principal prerequisite for studies of neurocognitive reserve in delirium. Serum biomarkers may be an important approach, but more research is needed in this area.⁸⁵

A Rationale for Studying Neurocognitive Reserve in Delirium

Delirium provides many unique characteristics which make the examination of the contribution of neurocognitive reserve particularly compelling (See Table 3). To date, brain and cognitive reserve have been studied primarily in chronic, degenerative conditions with extended preclinical phases, which greatly complicate the study of reserve. Thus, studying neurocognitive reserve in delirium, an acute condition without a long prodromal phase, may provide important insights into the role of neurocognitive reserve in cognitive decline. Moreover, the fact that delirium is often due to acute and overwhelming physiological insults may overcome some of the inherent biases in diagnosis and establishing baseline status. The fact that delirium often has a catastrophic acute phase with poor prognosis (where brain reserve may play a larger role) versus a more indolent phase where recovery potential may facilitate the examination of the mechanism of neurocognitive reserve. Finally, the preventable nature of delirium and its associated long-term adverse consequences, along with the high potential for recovery, heighten the clinical relevance of better understanding the contribution of neurocognitive reserve to its incidence and clinical course.

TABLE 3.

Unique Characteristics of Delirium Contributing to the Study of Reserve

Delirium Characteristic	Application to Brain and Cognitive Reserve
Acute onset, without long prodromal phase	Facilitates establishing baseline status
	Avoids long preclinical phase of chronic processes such as Alzheimer disease
Catastrophic medical insult	May help to minimize biases in detection and diagnosis; less dependence on socioeconomic status
Clinical course with initial poor prognosis and later long-term recovery	May allow separate examination of brain (important early on) and cognitive (important during recovery) components
Preventable nature	Facilitates examination of specific reserve components that may contribute and be amenable to intervention
Large potential for recovery	Highlights clinical importance of identifying reserve components that contribute to recovery potential

Conclusions

To move the concept of neurocognitive reserve forward generally, and the study of reserve in delirium specifically, the field must advance in definitions and refinements of theory, indicators, methodologic approaches, and intervention strategies. Pathophysiologic investigations, including neuroimaging and animal studies, will be critical for defining mechanisms of neurocognitive reserve in the context of delirium. Finally, intervention studies will be of fundamental clinical importance to determine whether reserve can be increased, and thus, incur direct benefits to our older population for the prevention of delirium and long-term cognitive decline. We propose a research agenda with some key research questions to explore reserve in delirium.

• Defining neurocognitive reserve in delirium:

  • ◦
    What are the causes of neurocognitive reserve, and how is neurocognitive reserve manifested? This is an issue of conceptualization and measurement. For example, educational attainment may predict higher levels of neurocognitive reserve, but as currently conceptualized high educational attainment is not a consequence of higher levels of neurocognitive reserve.
  • ◦
    How does neurocognitive reserve influence the occurrence, course and consequence of delirium? Does neurocognitive reserve confer resistance to delirium (lower delirium incidence), and/or promote recovery after delirium (shorter delirium duration or severity)?
  • ◦
    How does neurocognitive reserve in delirium differ from its role in other acute insults such as head trauma or stroke and in more chronic insults like dementia?

• Construct validation: Can the role of neurocognitive reserve be distinguished from other fundamental causes of poor health outcomes in delirium or from other fundamental causes of neuropsychiatric disorder?

• Measurement of neurocognitive reserve: How do we measure neurocognitive reserve in delirium? How can the discrepancy between observed and expected performance be operationalized in delirium? What are the best interview, laboratory, neuroimaging indicators for indexing the degree of neuropathology in delirium?

• Contributing factors: What are the behavioral, environmental, or genetic contributors to neurocognitive reserve in delirium? How do educational level, occupation, childhood IQ, socioeconomic status, exercise, activities, health habits, etc. contribute to neurocognitive reserve in delirium? Do depression or mental illness influence neurocognitive reserve?

• Cross-cultural measures: How do we adapt measures of neurocognitive reserve in delirium across cultures, birth cohorts, or other major population sub-groups

• Pathophysiology

  • ◦
    Functional neuroimaging: Can activation studies allow us to better understand the mechanisms of neurocognitive reserve in delirium (alternate pathways, neurogenesis, compensatory mechanisms)? Can we quantify neurocognitive reserve?
  • ◦
    Laboratory or electrophysiologic markers: Can we identify markers (e.g., cytokines, C-reactive protein, serum anticholinergic assays, cortisol levels, neurotransmitter levels, evoked potentials) that will correlate with degree of pathology in delirium?
  • ◦
    Neurotransmitter sensitive imaging: Using nuclear medicine studies or pharmacologic manipulation studies (such as anticholinergic or dopaminergic challenges) combined with functional neuroimaging, can we gain understanding of neurotransmitter abnormalities influencing neurocognitive in delirium?
  • ◦
    Animal model: Can we develop an animal model for neurocognitive reserve in delirium, such as raising animals in enriched environments and subjecting them to a delirium-inducing stimulus (e.g., drug or inflammatory challenge)?

• Neuropathological markers: Can we identify neuropathological markers for delirium, such as on brain biopsy or autopsy?

• Intervention

  • ◦Delirium prevention: Can methods to increase neurocognitive reserve (e.g., education, activities) prevent delirium? ⁸⁶ What are the most effective intervention strategies and dosages, and how late in life can these interventions begin and still make a difference?
  • ◦Pharmacologic treatment: Do dementia-approved drugs (e.g., donepezil, memantine) prevent delirium by increasing neurocognitive reserve? Are there other pharmacologic treatments that might influence cognitive or neurocognitive reserve in delirium, such as anti-inflammatory agents, anti-platelet agents, dopamine antagonists, antioxidants?

Delirium provides a unique opportunity to better understand the concept of neurocognitive reserve. The proposed studies will allow us to better understand the role of neurocognitive reserve in cognitive functioning more generally, and importantly, offer the potential to identify effective interventions to forestall cognitive decline in late life.

Neurocognitive reserve is probably modifiable.¹⁵ Interventions are available that may boost neurocognitive reserve. For example, mental training^87-90 and physical exercise⁹¹ have been shown in experimental studies to improve cognition and functional outcomes. Also, public policy priorities might influence neurocognitive reserve for future cohorts of older adults. Natural experiments of State variation in compulsory schooling laws suggests a large and causal effect of greater education on memory functioning in late life.⁹² Therefore, policy initiatives to mandate increased formal education are justified, and may serve to enhance the cognitive and functional health of future generations as they approach late life.