The Epidemiology of Delirium: Challenges and Opportunities for Population Studies
2013; Elsevier BV; Volume: 21; Issue: 12 Linguagem: Inglês
10.1016/j.jagp.2013.04.007
ISSN1545-7214
AutoresDaniel Davis, Stefan H. Kreisel, Graciela Muñiz‐Terrera, Andrew Hall, Alessandro Morandi, Malaz Boustani, Karin J. Neufeld, Hochang B. Lee, Alasdair M. J. MacLullich, Carol Brayne,
Tópico(s)Alcoholism and Thiamine Deficiency
ResumoDelirium is a serious and common acute neuropsychiatric syndrome that is associated with short- and long-term adverse health outcomes. However, relatively little delirium research has been conducted in unselected populations. Epidemiologic research in such populations has the potential to resolve several questions of clinical significance in delirium. Part 1 of this article explores the importance of population selection, case-ascertainment, attrition, and confounding. Part 2 examines a specific question in delirium epidemiology: What is the relationship between delirium and trajectories of cognitive decline? This section assesses previous work through two systematic reviews and proposes a design for investigating delirium in the context of longitudinal cohort studies. Such a design requires robust links between community and hospital settings. Practical considerations for case-ascertainment in the hospital, as well as the necessary quality control of these programs, are outlined. We argue that attention to these factors is important if delirium research is to benefit fully from a population perspective. Delirium is a serious and common acute neuropsychiatric syndrome that is associated with short- and long-term adverse health outcomes. However, relatively little delirium research has been conducted in unselected populations. Epidemiologic research in such populations has the potential to resolve several questions of clinical significance in delirium. Part 1 of this article explores the importance of population selection, case-ascertainment, attrition, and confounding. Part 2 examines a specific question in delirium epidemiology: What is the relationship between delirium and trajectories of cognitive decline? This section assesses previous work through two systematic reviews and proposes a design for investigating delirium in the context of longitudinal cohort studies. Such a design requires robust links between community and hospital settings. Practical considerations for case-ascertainment in the hospital, as well as the necessary quality control of these programs, are outlined. We argue that attention to these factors is important if delirium research is to benefit fully from a population perspective. Epidemiology is concerned with interrelationships between populations, exposures, and outcomes. The goal of the current article is to explore how the application of epidemiologic principles might provide opportunities for developments in delirium research. Epidemiology is able to address fundamental clinical questions in delirium:•Who gets delirium? What are the risk factors that lead to its development? Who is predisposed? What are the precipitants?•What is the natural history? How long might it last? What are the long-term outcomes? Are any adverse sequelae independent of the general consequences of systemic illness, trauma, surgery, or drug treatments?•Is there an association with dementia? How strong is this association? Does delirium affect trajectories of cognitive decline? Most of these questions have been addressed by studies in a range of settings. However, very little delirium research has been undertaken from a population-based perspective. This is essential if we hope to contextualize the many strands of investigation, otherwise limited by virtue of selected samples, within a common denominator.1Brayne C. Davis D. Making Alzheimer's and dementia research fit for populations.Lancet. 2012; 380: 1441-1443Abstract Full Text Full Text PDF PubMed Scopus (70) Google Scholar This article includes two parts: (1) a theoretical framework for epidemiologic research relevant to all older adults, namely: population selection, case-ascertainment, attrition (loss to follow-up), and confounding; and (2) a discussion on a critical question in delirium research: What is the relationship between delirium and trajectories of cognitive decline? Accordingly, it includes two systematic reviews: (1) the descriptive epidemiology of delirium in population-based studies; and (2) the impact of delirium on cognitive outcomes. These identify gaps, which lead to recommendations on how such an epidemiologic study of delirium and trajectories of cognitive decline might be practically achieved. We consider how to standardize and quality-control assessments of individuals with delirium. Thus, a range of specific clinical and organizational questions can be addressed. In considering the importance of defining a population, we are asking: Is the chosen population representative of the full spectrum of persons with delirium in that population? For example, if we are studying incidence of postoperative delirium in patients aged 70 years and older with urinary tract infections, are the individuals in the study representative of everyone with delirium or are there biases that arise because this is a relatively easy group to identify and recruit? How does the approach to sampling enable a valid capture of the chosen population? These are critical questions because the provenance of the sample population has the potential to systematically bias findings both in magnitude and direction. The majority of studies in delirium have been undertaken in specific hospital settings and often among patients with particular medical or surgical conditions.2Siddiqi N. House A.O. Holmes J.D. Occurrence and outcome of delirium in medical in-patients: a systematic literature review.Age Ageing. 2006; 35: 350-364Crossref PubMed Scopus (746) Google Scholar, 3Witlox J. Eurelings L.S. De Jonghe J.F. et al.Delirium in elderly patients and the risk of postdischarge mortality, institutionalization, and dementia: a meta-analysis.JAMA. 2010; 304: 443-451Crossref PubMed Scopus (1060) Google Scholar Together, these studies indicate that delirium is a common problem in inpatients and is associated with serious adverse outcomes, such as increased mortality, institutionalization, and dementia. However, there are three limitations to the inferences that can be drawn about delirium as a whole in the existing literature. First, one cannot assume that all persons with delirium from a given population will actually present to the particular hospital from which the respondents come. Second, once in the hospital, there is only retrospective information on a person's cognitive and functional status. This lack of reliable data on preadmission status makes it difficult to ascertain delirium (and pre-existing dementia) because the diagnosis requires determination of acute change in mental status. Third, the referral and selection bias inherent in hospital-based studies with particular subgroups of people with delirium leads to questionable generalizability or often conflicting findings across studies. An example of the importance of working with an unselected population is evident from the findings of the Oxfordshire Community Stroke Project (OCSP)4Bamford J. Sandercock P. Dennis M. et al.A prospective study of acute cerebrovascular disease in the community: the Oxfordshire Community Stroke Project—1981-86. 2. Incidence, case fatality rates and overall outcome at one year of cerebral infarction, primary intracerebral and subarachnoid haemorrhage.J Neurol Neurosurg Psychiatry. 1990; 53: 16-22Crossref PubMed Scopus (702) Google Scholar, 5Bamford J. Sandercock P. Dennis M. et al.A prospective study of acute cerebrovascular disease in the community: the Oxfordshire Community Stroke Project 1981-86. 1. Methodology, demography and incident cases of first-ever stroke.J Neurol Neurosurg Psychiatry. 1988; 51: 1373-1380Crossref PubMed Scopus (416) Google Scholar and its successor, the Oxford Vascular Study (OXVASC).6Rothwell P.M. Coull A.J. Giles M.F. et al.Change in stroke incidence, mortality, case-fatality, severity, and risk factors in Oxfordshire, UK from 1981 to 2004 (Oxford Vascular Study).Lancet. 2004; 363: 1925-1933Abstract Full Text Full Text PDF PubMed Scopus (836) Google Scholar A working definition for population-based study might be: "a study where all subgroups of the population are sampled, regardless of disease or residential status."7Zaccai J. Ince P. Brayne C. Population-based neuropathological studies of dementia: design, methods and areas of investigation—a systematic review.BMC Neurol. 2006; 6: 2Crossref PubMed Scopus (82) Google Scholar These studies of stroke incidence made comprehensive efforts to ascertain all cases of transient ischemic attack (TIA) or stroke from a defined population registered at general practitioners' (GP) offices, where virtually all primary care in the United Kingdom is delivered. Each participating surgery (clinic) maintained close personal contact with the study, and collaborating GPs reported suspected cases to the study as soon as patients presented. If participants were not admitted to the hospital directly, they were assessed on the day of referral in a dedicated research clinic or at the participant's own home. All computerized diagnostic codes were reviewed, strengthened by record linkage systems between primary and secondary care. Hospital and emergency department presentations were reviewed daily, and all deaths out of hospital were identified via the coroner's office. This strategy to include all cases from the general population resulted in great advances in understanding the prognosis and outcomes from TIA and stroke, precisely because it included the full range of persons with acute neurovascular events. In a systematic review of studies reporting the risk of early stroke after TIA, it is clear that population-based studies had much higher estimates of early recurrence (within 7 days) compared with those samples presenting solely to specialist stroke services (proportion (95% confidence interval [CI] recurring within 7 days in population-based studies versus specialist stroke services: 10.4% [8.1–12.6)] versus 0.9% [0.0–1.9], respectively).8Giles M.F. Rothwell P.M. Risk of stroke early after transient ischaemic attack: a systematic review and meta-analysis.Lancet Neurology. 2007; 6: 1063-1072Abstract Full Text Full Text PDF PubMed Scopus (527) Google Scholar It is now clear that the relationship between TIA and early stroke can be predicted by using a clinical risk score.9Rothwell P.M. Giles M.F. Flossmann E. et al.A simple score (ABCD) to identify individuals at high early risk of stroke after transient ischaemic attack.Lancet. 2005; 366: 29-36Abstract Full Text Full Text PDF PubMed Scopus (511) Google Scholar, 10Giles M.F. Rothwell P.M. Systematic review and pooled analysis of published and unpublished validations of the ABCD and ABCD2 transient ischemic attack risk scores.Stroke. 2010; 41: 667-673Crossref PubMed Scopus (106) Google Scholar These findings had a major impact in the planning of stroke services and in improving outcomes for patients.11Rothwell P.M. Giles M.F. Chandratheva A. et al.Effect of urgent treatment of transient ischaemic attack and minor stroke on early recurrent stroke (EXPRESS study): a prospective population-based sequential comparison.Lancet. 2007; 370: 1432-1442Abstract Full Text Full Text PDF PubMed Scopus (913) Google Scholar For delirium research, we need to consider how explicitly the population is defined. To understand how delirium relates to adverse cognitive outcomes, an optimal design would start with a broad, unselected denominator (i.e., a true population-based study) followed up with serial cognitive, mood, and functional assessments. This method would result in the identification of a comprehensive range of symptoms and severities, and would establish what happens, to whom, and when. Of course, ensuring that a study population is comprehensive in this way requires substantial effort, but there are gains of equal degree in terms of achieving results with external generalizability. To reliably track states of health in populations, the definition of exposures and outcomes of interest must be standardized. For psychiatric syndromes, the reference-standard definition is necessarily a set of clinically agreed on descriptions of psychopathology rather than any objective measures. However, the possibility that biomarkers might eventually contribute to case-ascertainment is reviewed in the following discussion. There are some differences between the International Classification of Diseases (World Health Organization) and the Diagnostic and Statistical Manual of Mental Disorders (DSM) (American Psychiatric Association) definitions of delirium, and these have an impact on case-ascertainment.12Cole M.G. Dendukuri N. McCusker J. et al.An empirical study of different diagnostic criteria for delirium among elderly medical inpatients.J Neuropsychiatry Clin Neurosci. 2003; 15: 200-207Crossref PubMed Scopus (61) Google Scholar, 13Liptzin B. Levkoff S.E. Cleary P.D. et al.An empirical study of diagnostic criteria for delirium.Am J Psychiatry. 1991; 148: 454-457Crossref PubMed Google Scholar, 14Laurila J.V. Pitkala K.H. Strandberg T.E. et al.Impact of different diagnostic criteria on prognosis of delirium: a prospective study.Dement Geriatr Cogn Disord. 2004; 18: 240-244Crossref PubMed Scopus (43) Google Scholar These definitions evolve with each revision and are therefore not stable over time. More problematic is that these clinical criteria have the potential to be interpreted differently by individual clinicians. For example, the threshold for impairment on cognitive testing in delirium may decrease with age, in line with a belief that some deficit is expected, and thus not abnormal, in older age.15Brayne C. Research and Alzheimer's disease: an epidemiological perspective.Psychol Med. 1993; 23: 287-296Crossref PubMed Scopus (32) Google Scholar It is worth examining the precision of the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision, description, exploring the difficulty with using the definition for standardizing case-ascertainment in research. Although successive revisions are supposed to be based on epidemiologic field testing, only two studies were conducted in tertiary hospital samples (total n = 560) for Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV).13Liptzin B. Levkoff S.E. Cleary P.D. et al.An empirical study of diagnostic criteria for delirium.Am J Psychiatry. 1991; 148: 454-457Crossref PubMed Google Scholar, 16Johnson J.C. Gottlieb G.L. Sullivan E. et al.Using DSM-III criteria to diagnose delirium in elderly general medical patients.J Gerontol. 1990; 45: M113-M119Crossref PubMed Scopus (84) Google Scholar Deficits in attention have been recognized as a core diagnostic feature since publication of Diagnostic and Statistical Manual of Mental Disorders, Third Edition Revised (DSM-III-R) (Criterion A) (Box 1). It supplanted the previous description "clouding of consciousness" because the latter term was regarded as being too imprecise.17Lipowski Z.J. Transient cognitive disorders (delirium, acute confusional states) in the elderly.Am J Psychiatry. 1983; 140: 1426-1436Crossref PubMed Scopus (311) Google Scholar However, it is not clear what should constitute a minimum threshold for attentional deficits in the diagnosis of delirium using DSM-III-R and above.18Lowery D.P. Wesnes K. Brewster N. et al.Subtle deficits of attention after surgery: Quantifying indicators of sub syndrome delirium.Int J Geriatr Psychiatry. 2010; 25: 945-952Crossref PubMed Scopus (12) Google Scholar Moreover, patients who present with a reduced level of consciousness in an acute setting are often not included in delirium studies if the severity of their impairments means that they cannot undergo cognitive testing. These two unresolved but crucial issues reflect the general scarcity of research on the neuropsychology of delirium.19MacLullich A.M.J. Hall R.J. Who understands delirium?.Age Ageing. 2011; 40: 412-414Crossref PubMed Scopus (33) Google ScholarBox 1Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Criteria for DeliriumTabled 1A. Disturbance of consciousness (i.e., reduced clarity of awareness of the environment) with reduced ability to focus, sustain, or shift attention.B. A change in cognition or the development of a perceptual disturbance that is not better accounted for by a pre-existing, established, or evolving dementia.C. The disturbance develops over a short period of time (usually hours to days) and tends to fluctuate during the course of the day.D. There is evidence from the history, physical examination, or laboratory findings that the disturbance is caused by the direct physiologic consequences of a general medical condition. Open table in a new tab Tabled 1A. Disturbance of consciousness (i.e., reduced clarity of awareness of the environment) with reduced ability to focus, sustain, or shift attention.B. A change in cognition or the development of a perceptual disturbance that is not better accounted for by a pre-existing, established, or evolving dementia.C. The disturbance develops over a short period of time (usually hours to days) and tends to fluctuate during the course of the day.D. There is evidence from the history, physical examination, or laboratory findings that the disturbance is caused by the direct physiologic consequences of a general medical condition. Open table in a new tab Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision, also requires a change in cognition or perceptual disturbance (Criterion B). However, the extent to which delirium may have a differential effect on domains of cognition or perception is complex and not specified. Neuropsychiatric symptoms such as motor 20Meagher D.J. Leonard M. Donnelly S. et al.A longitudinal study of motor subtypes in delirium: relationship with other phenomenology, etiology, medication exposure and prognosis.J Psychosom Res. 2011; 71: 395-403Abstract Full Text Full Text PDF PubMed Scopus (127) Google Scholar or sleep–wake21Jabbar F. Leonard M. Meehan K. et al.Neuropsychiatric and cognitive profile of patients with DSM-IV delirium referred to an old age psychiatry consultation-liaison service.Int Psychogeriatr. 2011; 23: 1167-1174Crossref PubMed Scopus (26) Google Scholar disturbance are frequently present but not specific for delirium. Affective symptoms, thought disorder, and perceptual disturbances are also recognized as part of Criterion B, and operationalizing these features would serve to maximize sensitivity of detection. Criterion C states that symptoms should be acute (hours to days) and fluctuate over the course of the day. These features are highly specific to delirium. However, by their nature, they make ascertainment more difficult because a test score may vary over periods of hours or even minutes. Multiple assessments per day could increase detection of deficits as well as eliciting fluctuation but may be impractical. Currently, best practice is to use tools that attempt to capture relevant information (e.g., informant history, clinical case notes) in the period preceding the assessment. Specifying that delirium is due to an underlying medical disorder fulfills Criterion D. However, it is unclear what should actually constitute "evidence" for cause and effect. For the vast majority of cases, acute medico-surgical events (e.g., urinary tract infection) and delirium are temporarily linked. However, because the pathophysiology of delirium remains elusive,22MacLullich A.M. Ferguson K.J. Miller T. et al.Unravelling the pathophysiology of delirium: a focus on the role of aberrant stress responses.J Psychosom Res. 2008; 65: 229-238Abstract Full Text Full Text PDF PubMed Scopus (263) Google Scholar level of evidence for etiologic links remains subject to scepticism. In addition, often multiple etiologies are demonstrable over the course of delirium23Laurila J.V. Laakkonen M.L. Tilvis R.S. et al.Predisposing and precipitating factors for delirium in a frail geriatric population.J Psychosom Res. 2008; 65: 249-254Abstract Full Text Full Text PDF PubMed Scopus (86) Google Scholar but may be unidentifiable in ∼10%.24Meagher D.J. MacLullich A.M.J. Laurila J.V. Defining delirium for the International Classification of Diseases, 11th Revision.J Psychosom Res. 2008; 65: 207-214Abstract Full Text Full Text PDF PubMed Scopus (42) Google Scholar It is not known if the precipitant influences the phenomenologic presentation. The boundaries for the delirium syndrome become more complex when considering co-morbid dementia. DSM separates the delirium and dementia definitions, but the problem of identifying one superimposed on the other remains. This is crucial because delirium can be missed, under an assumption that observed cognitive deficits are due to dementia. When delirium and dementia co-exist, the delirium symptoms (e.g., prominent inattention with fluctuating deficits) are thought to dominate the presentation over the impairments seen in dementia; this theory has been reviewed in detail elsewhere.24Meagher D.J. MacLullich A.M.J. Laurila J.V. Defining delirium for the International Classification of Diseases, 11th Revision.J Psychosom Res. 2008; 65: 207-214Abstract Full Text Full Text PDF PubMed Scopus (42) Google Scholar, 25Meagher D.J. Leonard M. Donnelly S. et al.A comparison of neuropsychiatric and cognitive profiles in delirium, dementia, comorbid delirium-dementia and cognitively intact controls.J Neurol Neurosurg Psychiatry. 2010; 81: 876-881Crossref PubMed Scopus (80) Google Scholar, 26Blazer D.G. van Nieuwenhuizen A.O. Evidence for the diagnostic criteria of delirium: an update.Curr Opin Psychiatry. 2012; 25: 239-243Crossref PubMed Scopus (57) Google Scholar However, much of the delirium fieldwork explicitly excluded persons with dementia; therefore, the resultant conceptualization overemphasizes features that are more likely to be reported in cognitively intact persons (e.g., psychotic symptoms). Conversely, delirium scales that include assessments of memory or other cognitive deficits known to be present in dementia (such as the Delirium Rating Scale–Revised-98)27Trzepacz P.T. Mittal D. Torres R. et al.Validation of the Delirium Rating Scale-revised-98: comparison with the delirium rating scale and the cognitive test for delirium.J Neuropsychiatry Clin Neurosci. 2001; 13: 229-242Crossref PubMed Scopus (475) Google Scholar may be confounded by the presence of dementia. Moreover, some delirium assessment instruments have been validated in groups from which dementia patients were excluded. One consequence is that individuals perform poorly on the memory subscale because of dementia, regardless of whether delirium is also present. Currently, it is not known if delirium and dementia can be distinguished in a cross-sectional assessment on cognitive and phenomenologic grounds alone, but some studies suggest that this might be possible.28Brown L.J. Fordyce C. Zaghdani H. et al.Detecting deficits of sustained visual attention in delirium.J Neurol Neurosurg Psychiatry. 2011; 82: 1334-1340Crossref PubMed Scopus (41) Google Scholar, 29Brown L.J.E. McGrory S. McLaren L. et al.Cognitive visual perceptual deficits in patients with delirium.J Neurol Neurosurg Psychiatry. 2009; 80: 594-599Crossref PubMed Scopus (25) Google Scholar, 30Chester J.G. Beth Harrington M. Rudolph J.L. Serial administration of a modified richmond agitation and sedation scale for delirium screening.J Hosp Med. 2011; 7: 450-453Crossref PubMed Scopus (103) Google Scholar The chief difficulty with operationalizing delirium is that the boundaries of the main constructs are not clearly defined. DSM does not specify duration, severity, minimum thresholds, or which symptoms should fluctuate over which time frames. However, empiric data suggest that each of these parameters may influence outcomes and therefore perhaps define prognostic groups (Table 1).24Meagher D.J. MacLullich A.M.J. Laurila J.V. Defining delirium for the International Classification of Diseases, 11th Revision.J Psychosom Res. 2008; 65: 207-214Abstract Full Text Full Text PDF PubMed Scopus (42) Google Scholar, 26Blazer D.G. van Nieuwenhuizen A.O. Evidence for the diagnostic criteria of delirium: an update.Curr Opin Psychiatry. 2012; 25: 239-243Crossref PubMed Scopus (57) Google Scholar Further detailed population-based fieldwork involving increased use of standardized definitions and measurements with objective high reliability is essential if case definitions are to describe useful phenotypes. Despite these limitations, in the research setting, the aim is to operationalize these criteria so that case-ascertainment can be achieved in a consistent manner.Table 1Clinical Features in Delirium Not Currently Defined by DSM Criteria With a Theoretical Influence on Determining Prognostic CategoriesEffect on PrognosisCommentReferencesMotoric subtypesHypoactive delirium associated with higher mortality, especially with co-morbid dementiaMotoric assessment, including accelerometer-based measures have scope to inform prognostic categories79O'Keeffe S.T. Clinical subtypes of delirium in the elderly.Dementia and Geriatric Cognitive Disorders. 1999; 10: 380-385Crossref PubMed Scopus (74) Google Scholar, 80Yang F.M. Marcantonio E.R. Inouye S.K. et al.Phenomenological subtypes of delirium in older persons: patterns, prevalence, and prognosis.Psychosomatics. 2009; 50: 248-254Abstract Full Text Full Text PDF PubMed Scopus (111) Google Scholar, 81Meagher D. Motor subtypes of delirium: Past, present and future.Int Rev Psychiatry. 2009; 21: 59-73Crossref PubMed Scopus (117) Google ScholarDurationMinimum and maximum duration unclearDelirium may evolve into dementia. Short-term versus persistent delirium proposed in DSM-5 (threshold not specified)Temporal fluctuationsSpecifying short fluctuations (hours) favors identification of hyperactive over hypoactive subtypeHypoactive delirium has poorer prognosis; therefore, any specification of temporal fluctuations should take this into accountSeverityClinical rating scales in existence (e.g., DRS-98, MDAS, Delirium Index). Higher scores associated with worse outcomesCategories of severity might be incorporated into diagnostic criteria82Adamis D. Treloar A. Martin F.C. et al.Recovery and outcome of delirium in elderly medical inpatients.Arch Gerontol Geriatr. 2006; 43: 289-298Abstract Full Text Full Text PDF PubMed Scopus (89) Google ScholarSubsyndromal deliriumHigher mortality and worse cognitive outcomes compared to normal controlsVariably defined; represents a state between normality and full delirium syndrome. Current definition of delirium might perhaps be broadened to include milder deficits83Cole M.G. McCusker J. Dendukuri N. et al.The prognostic significance of subsyndromal delirium in elderly medical inpatients.J Am Geriatr Soc. 2003; 51: 754-760Crossref PubMed Scopus (204) Google Scholar, 84Meagher D. Adamis D. Trzepacz P. et al.Features of subsyndromal and persistent delirium.Br J Psychiatry. 2012; 200: 37-44Crossref PubMed Scopus (67) Google ScholarNotes: DRS-98: Delirium Rating Scale–Revised-98; DSM-5: fifth edition of the Diagnostic and Statistical Manual of Mental Disorders; MDAS: Memorial Delirium Assessment Scale. Open table in a new tab Notes: DRS-98: Delirium Rating Scale–Revised-98; DSM-5: fifth edition of the Diagnostic and Statistical Manual of Mental Disorders; MDAS: Memorial Delirium Assessment Scale. Biomarkers have been widely considered in dementia, for example, in the hope that a greater understanding of dementia pathophysiology might be able to contribute to case-ascertainment or even supplant the current clinical reference standard.31Sunderland T. Hampel H. Takeda M. et al.Biomarkers in the diagnosis of Alzheimer's disease: are we ready?.J Geriatr Psychiatry Neurol. 2006; 19: 172-179Crossref PubMed Scopus (54) Google Scholar, 32Dubois B. Feldman H.H. Jacova C. et al.Research criteria for the diagnosis of Alzheimer's disease: revising the NINCDS-ADRDA criteria.Lancet Neurology. 2007; 6: 734-746Abstract Full Text Full Text PDF PubMed Scopus (3163) Google Scholar, 33McKhann G.M. Knopman D.S. Chertkow H. et al.The diagnosis of dementia due to Alzheimer's disease: recommendations from the National Institute on Aging-Alzheimer's Association workgroups on diagnostic guidelines for Alzheimer's disease.Alzheimers Dement. 2011; 7: 263-269Abstract Full Text Full Text PDF PubMed Scopus (7966) Google Scholar There has been substantial progress in the field; for example, identifying amyloid burden in vivo34Klunk W.E. Engler H. Nordberg A. et al.Imaging brain amyloid in Alzheimer's disease with Pittsburgh Compound-B.Ann Neurol. 2004; 55: 306-319Crossref PubMed Scopus (3329) Google Scholar and putative markers of neurodegeneration, among others.35Blennow K. Hampel H. CSF markers for incipient Alzheimer's disease.Lancet Neurology. 2003; 2: 605-613Abstract Full Text Full Text PDF PubMed Scopus (1002) Google Scholar, 36Mosconi L. Brain glucose metabolism in the early and specific diagnosis of Alzheimer's disease. FDG-PET studies in MCI and AD.Eur J Nucl Med Mol Imaging. 2005; 32: 486-510Crossref PubMed Scopus (622) Google Scholar However, such work has only ever been generalizable to the selected populations able to tolerate procedures such as positron emission tomography/magnetic resonance imaging or lumbar puncture.1Brayne C. Davis D. Making Alzheimer's and dementia research fit for populations.Lancet. 2012; 380: 1441-1443Abstract Full Text Full Text PDF PubMed Scopus (70) Google Scholar There is a real need for biomarker research to be validated within the context of a general population before they can be proposed as part of a new reference standard. Current plasma biomarker candidates such as apolipoprotein E, insulin-like growth factor-1, and S-100β
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