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The literature on Alzheimer’s disease (AD) provides little data about long-term cognitive course trajectories. We identify global cognitive outcome trajectories and associated predictor variables that may inform clinical research and care.
Data derived from the National Alzheimer’s Coordinating Center (NACC) Uniform Data Set were used to examine the cognitive course of persons with possible or probable AD, a Mini-Mental State Examination (MMSE) of ≥10, and complete annual assessments for 5 years.
Thirty-six Alzheimer’s Disease Research Centers.
Four hundred and fourteen persons.
We used a hybrid approach comprising qualitative analysis of MMSE trajectory graphs that were operationalized empirically and binary logistic regression analyses to assess 19 variables’ associations with each trajectory. MMSE scores of ±3 points or greater were considered clinically meaningful.
Five distinct cognitive trajectories were identified: fast decliners (32.6%), slow decliners (30.7%), zigzag stable (15.9%), stable (15.9%), and improvers (4.8%). The decliner groups had three subtypes: curvilinear, zigzag, and late decline. The fast decliners were associated with female gender, lower baseline MMSE scores, a shorter illness duration, or receiving a cognitive enhancer. An early MMSE decline of ≥3 points predicted a worse outcome. A higher rate of traumatic brain injury, the absence of an ApoE ϵ4 allele, and male gender were the strongest predictors of favorable outcomes.
Our hybrid approach revealed five distinct cognitive trajectories and a variegated pattern within the decliners and stable/improvers that was more consistent with real-world clinical experience than prior statistically modeled studies. Future investigations need to determine the consistency of the distribution of these categories across settings.
This study investigated the characteristics of subjective memory complaints (SMCs) and their association with current and future cognitive functions.
A cohort of 209 community-dwelling individuals without dementia aged 47–90 years old was recruited for this 3-year study. Participants underwent neuropsychological and clinical assessments annually. Participants were divided into SMCs and non-memory complainers (NMCs) using a single question at baseline and a memory complaints questionnaire following baseline, to evaluate differential patterns of complaints. In addition, comprehensive assessment of memory complaints was undertaken to evaluate whether severity and consistency of complaints differentially predicted cognitive function.
SMC and NMC individuals were significantly different on various features of SMCs. Greater overall severity (but not consistency) of complaints was significantly associated with current and future cognitive functioning.
SMC individuals present distinctive features of memory complaints as compared to NMCs. Further, the severity of complaints was a significant predictor of future cognition. However, SMC did not significantly predict change over time in this sample. These findings warrant further research into the specific features of SMCs that may portend subsequent neuropathological and cognitive changes when screening individuals at increased future risk of dementia.
At the present time, there is increasing recognition and understanding of the mild cognitive impairment (MCI) entity as a stage which is a frequent precursor and harbinger of subsequently manifest Alzheimer's disease (AD) and, perhaps, other related conditions, such as vascular dementia (Gauthier et al., 2006). MCI has been defined in two disparate but generally compatible ways in the current literature (see Reisberg et al., 2008 (this issue), for a more complete historical overview of MCI). These two definitional approaches might be termed: (a) the clinical approach to MCI, and (b) the clinical plus psychometric approach to MCI.
Descriptions of dementia can be traced to antiquity. Prichard (1837) described four dementia stages and Kral (1962) described a “benign senescent forgetfulness” condition. The American Psychiatric Association's DSM-III (1980) identified an early dementia stage.
In 1982, the Clinical Dementia Rating (CDR) and the Global Deterioration Scale (GDS) were published, which identified dementia antecedents. The CDR 0.5 “questionable dementia” stage encompasses both mild dementia and earlier antecedents. GDS stage 3 described a predementia condition termed “mild cognitive decline” or, alternatively, beginning in 1988, “mild cognitive impairment” (MCI). This GDS stage 3 MCI condition is differentiated from both a preceding GDS stage 2, “subjective cognitive impairment” (SCI) stage and a subsequent GDS 4 stage of mild dementia.
GDS stage 3 MCI has been well characterized. For example, specific clinical concomitants, mental status and psychological assessment score ranges, behavioral and emotional changes, neuroimaging concomitants, neurological reflex changes, electrophysiological changes, motor and coordination changes, and changes in activities, accompanying GDS stage 3 MCI have been described.
Petersen and associates proposed a definition of MCI in 2001 which has been widely used (hereafter referred to as “Petersen's MCI”). Important differences between GDS stage 3 MCI and Petersen's MCI are that, because of denial, GDS stage 3 MCI does not require memory complaints. Also, GDS stage 3 MCI recognizes the occurrence of executive level functional deficits, which Petersen's MCI did not. Nevertheless, longitudinal and other studies indicate essential compatibility between GDS stage 3 MCI and Petersen's MCI duration and outcomes.
Global measures used in treatment trials in dementia encompass two distinct categories: (1) clinician's interview-based global severity scales, and (2) clinician's interview-based global change scales.
The global severity scales that have been used include: the Clinical Dementia Rating (CDR) and the related CDR-sum of boxes (CDR-SB), the Global Deterioration Scale (GDS), and the Functional Assessment Staging (FAST) procedure. The global severity scales are clearly useful in subject categorization in treatment trials, in part because they are relatively free of many of the sociocultural biases inherent in mental status and psychometric descriptors. Global severity scales can also be used to demonstrate therapeutic efficacy in terms of the general progression of the dementia process. These measures have also proven to be useful in sensitively assessing pharmacotherapeutic effects in Alzheimer's disease (AD) treatment trials. For example, in pivotal trials: (1) in Mild to Moderate AD, the GDS has shown significant change in response to medication, whereas the results on the Mini-mental State Examination (MMSE) were not significant, and (2) in Moderate to Severe AD, the FAST has shown significant pharmacotherapeutic efficacy, whereas the results using the MMSE were not significant.
The global change scales employed in dementia trials differ widely in assessment methodology. Clinical Global Impressions of Change (CGIC) scales do not have defined methodologies, whereas Clinician's Interview-Based Impression of Change Plus Caregiver Input (CIBIC-Plus) scales are much more elaborate. The CIBIC-Plus procedures require an independent clinician assessment and can provide independent, comprehensive evidence of therapeutic efficacy. The CIBIC-Plus procedure may also be useful in sensitively assessing efficacy in future prevention trials, for example in subjects with Subjective Cognitive Impairment. For Mild Cognitive Impairment (MCI), global severity scales already appear to be one modality for the sensitive assessment of change. The CIBIC-Plus procedures might also productively be applied in future MCI therapeutic trials.
Current knowledge with respect to the diagnosis of Alzheimer's disease (AD) is reviewed. There is agreement that AD is a characteristic clinicopathologic entity that is amenable to diagnosis. The diagnosis of AD should no longer be considered one of exclusion. Rather, the diagnostic process is one of recognition of the characteristic features of AD and of conditions that can have an impact on presentation or mimic aspects of the clinicopathologic picture. The present availability of improved prognosis, management, and treatment strategies makes the proper, and state-of-the-art, diagnosis of AD a clinical imperative in all medical settings. Concurrently, information regarding the relevance and applicability of current diagnostic procedures in diverse cultural settings must continue to accrue.
Reisberg: I would like to summarize very briefly. In the Consortium to Establish a Registry for Alzheimer's Disease (CERAD) study, one third of patients with Alzheimer's disease (AD) had concomitant cerebral vascular disease. This finding supports the original work of Tomlinson and Blessed, who indicated a similar percentage of patients with AD also had mixed cerebral vascular disease upon neuropathologic examination.
Behavioral and psychological symptoms of dementia (BPSD; Finkel et al., 1998) are receiving increased attention in the medical and scientific literature. These symptoms are a principal cause of distress and disability among patients with dementia and their caregivers. Numerous therapeutic studies examining the treatment of these symptoms are being conducted.
Background: General relationships between dotage and infancy and childhood have been acknowledged for more than two millennia. Recent findings indicate precise relationships between functional, praxic, and feeding changes in the course of the degenerative dementia of Alzheimer's disease (AD) and inverse corresponding developmental sequences. Similar inverse relationships between AD and human development can be described for cognition and language skills; for physiologic measures of electroencephalographic activity, brain glucose metabolism, and developmental neurologic reflex changes; and for the neuropathologic and neuroanatomic progression of these processes. In AD, these processes may be termed “retrogenesis.” The relevance of the retrogenesis model for AD management is explored. Method: The functional stages of AD can be translated into developmental age equivalents that can be utilized to explicate observed changes in the disease. Results: The retrogenesis-based developmental age model can usefully inform an understanding of the general care needs, emotional and behavioral changes, and activity needs of the AD patient. This model must be amended by necessary caveats regarding physical differences, variations in age-associated pathology, differences in social and societal reactions, and differences in background between AD patients and their developmental age “peers.” Conclusions: Knowledge of retrogenesis and the developmental age of the AD patients can form a nidus for the development of a nascent science of disease management. Such a science must ultimately incorporate not only appropriate caveats but also relevant universal human needs, such as those for dignity, love, and movement.
Staging methodologies are an essential tool in the assessment of disease severity in progressive dementing illness. Several different instruments have been developed for this purpose. One of the most widely used methodologies is the Global Deterioration Scale/Functional Assessment Staging (GDS/FAST) system. This system has been studied extensively and proven to be reliable and valid for staging dementia in Alzheimer's disease (AD) in diverse settings. One of the major advantages of this system is that it spans, demarcates, and describes the entire course of normal aging and progressive AD until the final substages of the disease process. Other advantages include: (a) greatly enhanced ability to track the longitudinal course of AD, (b) improved clinicopathologic observations of AD interrelationships, and (c) enhanced diagnostic, differential diagnostic, and prognostic information. This article presents a brief overview of the GDS/FAST staging system.
It is both an honor and a privilege to introduce the winners of the sixth biennial IPA Research Awards in Psychogeriatrics, sponsored by Bayer AG. On behalf of IPA and the entire psychogeriatric community, I want to thank Bayer for their very generous support of these awards since their inception in 1989.
This supplementary issue of International Psychogeriatrics, titled “Vascular Burden of the Brain,” is the product of a special meeting of the International Psychogeriatric Association (IPA), with involvement from Alzheimer's Disease International, the World Federation of Neurology Dementia Study Group, the United States Food and Drug Administration (FDA), and the European Commission for Pharmaceutical and Medicinal Compounds (CPMP). The meeting was held in Madrid in November 2001 and was a closed gathering of many leading international experts on various aspects of vascular brain disease. Attendees included basic scientists, psychiatrists, neurologists, epidemiologists, and neuroradiologists. This wealth of expertise, both from clinicians and scientists, emphasized the necessity for interdisciplinary research into vascular disorders of the brain that affect cognition and behavior. One aim of the meeting was to produce a position paper that summarized the current situation in this field, both highlighting recent advances and identifying important areas where further progress is required. This paper, entitled “Vascular Cognitive Impairment,” has been published in Lancet Neurology (O'Brien et al., Lancet Neurology, February 2003, 2, 11–20). This issue of International Psychogeriatrics contains the individual articles submitted by participants in the special IPA meeting in November 2001.
This article describes the results of studies conducted to determine the usefulness of reflex changes as markers of disease severity in Alzheimer's disease (AD). Standardized and quantified muscle stretch reflexes, cutaneous, reflexes, and developmental (primitive) reflexes were studied in normal older adults, in individuals with mild memory impairment, and in patients with AD, in all clinical severity stages as assessed with the Global Deterioration Scale (GDS), the Mini-Mental State Examination (MMSE), and the Functional Assessment Staging (FAST) procedure. Changes in frequency and intensity of these individual reflex variables, as well as of variables consisting of combinations of these individual reflexes, appeared to be sensitive indicators of the progression of AD. These neurological reflex variables showed high Pearson correlations with the GDS (.72), the MMSE (.74), and the FAST (.80). Standardized quantified neurological reflex measures are useful as noncognitive, education-independent, and culture-independent markers of the course of AD.
Whitehouse: In the USA, the Agency for Healthcare Policy and Research has recently issued guidelines for early recognition and assessment of dementia, which I think this group should aim to incorporate in its deliberations. Interestingly, to assess patient function, they selected an instrument from the literature called the FAQ, which as far as I am aware, is not widely known by people in the field. Would anyone like to comment on this test? These guidelines will influence GPs, because they will be made aware of the recommendations by government information leaflets.
Background: Activities of daily living (ADL) deficits are integral components of dementia disorders, and ADL measures are among the most robust markers of the course of Alzheimer's disease (AD). Despite this acknowledged importance, no clearly useful ADL instrument for cross-cultural application in pharmacologic trials in the early stages of AD had been available. Method: An international effort was launched to develop an ADL scale for pharmacologic trials in early AD. Steps taken from 1990 to the present included: (1) international scientific working group meetings and reviews, (2) reviews of existing measures, (3) collating of existent, nonredundant items, (4) querying experts for new items, (5) interviews with informants and subjects in the USA, France, and Germany, toward the identification of potential new items, (6) identification of an item pool based upon these procedures, (7) creation of a trial instrument, (8) piloting of this instrument, and (9) refinement of the scale based upon statistical analysis of the pilot data. Final item selection was based upon: (1) relevance for ≥ 80% of subjects in severity-stratified USA and German samples; (2) absence of gender and national biases; (3) significant (p < .05) discrimination between (a) normal versus mildly impaired and (b) mildly impaired versus moderately to moderately severely impaired subjects; and (4) Global Deterioration Scale (GDS) scores accounting for ≥ 12% of variance in the item after controlling for age and gender. Results: An ADL scale consisting of 40 items that correlate with the global and cognitive progress of AD is developed for international usage in pharmacologic trials in incipient, mild, moderate, and moderately severe AD. The scale contains 40 items falling within 13 ADL categories. The 40-item scale is shown to have .81 correlation with GDS staging,.81 with mental status assessment (Mini-Mental State Examination), and .81 with a psychometric test (the SKT) (p values < .001). Conclusion: This scale can be used to measure therapeutic response in AD.
Roses: I reviewed Professor Smith's and Dr. Jobst's data with them at Oxford, and we are really not concluding anything very different. The tests of state used in their study, in this case the computed tomographic (CT) scan, work on essentially all patients with Alzheimer's disease (AD), no matter what their ApoE genotype. The positive predictor value of an E4 in the 60% or 75% of patients with AD who have a positive E4 is 97%, but for those 35% or so who are negative, the test has no value at all. So, in comparing its diagnostic usefulness, there will always be a proportion of patients for whom the test has no value.
The Behavioral Pathology in Alzheimer's Disease Rating Scale (BEHAVE-AD) was specifically designed to assess behavioral and psychological symptoms of dementia (BPSD) that would be remediable to both psychologic and pharmacologic intervention. Furthermore, the BEHAVE-AD was designed to assess categories of symptoms that would respond in a cohesive (syndrome) manner in dementia patients, independently of effects of interventions on cognition and functioning. Current data indicate that the BEHAVE-AD does indeed assess a cohesive, cognition- and function independent syndrome in AD and in related dementias that is responsive to psychologic and appropriate pharmacologic intervention. Evidence is also increasing for differential responsiveness of this BPSD syndrome to select pharmacologic agents compared with nonspecific psychologic (placebo) intervention. This article reviews the evidence for this BPSD syndrome in dementia patients, as assessed with the BEHAVE-AD.
It is a privilege to announce on behalf of IPA the 7th Biannual IPA Research Awards in Psychogeriatrics. These awards are given for the best-submitted results of original, previously unpublished, research conducted in the field of psychogeriatrics. For the 2001 award competition, 35 submissions were received. These submissions came from 15 countries on five continents. Clearly, the review task is both rigorous and demanding, and I would like to commend the other referees who generously gave of their time and expertise for this competition. The referees were: Manfred Bergener from Germany; Henry Brodaty from Australia; Alistair Burns from England (UK); Vijay Chandra from India; Helen Fung-kum Chiu from Hong Kong; Edmund Chiu from Australia; Michael Davidson from Israel; Robin Eastwood from England (UK); Timo Erkinjuntti from Finland; Sanford Finkel from the United States; Mario Fioravanti from Italy; George Grossberg from the United States; Brian Lawlor from Ireland; Joao Carlos Barbosa Machado from Brazil; Burton Reifler from the United States; Karen Ritchie from France; Joel Sadavoy from Canada; and Michael Zaudig from Germany, in addition to myself, who also served as Chair of the IPA Research Awards Committee.