Melanie B. Shulman

A conceptual framework for research on subjective cognitive decline in preclinical Alzheimer's disease

There is increasing evidence that subjective cognitive decline (SCD) in individuals with unimpaired performance on cognitive tests may represent the first symptomatic manifestation of Alzheimers disease (AD). The research on SCD in early AD, however, is limited by the absence of common standards. The working group of the Subjective Cognitive Decline Initiative (SCD‐I) addressed this deficiency by reaching consensus on terminology and on a conceptual framework for research on SCD in AD. In this publication, research criteria for SCD in pre‐mild cognitive impairment (MCI) are presented. In addition, a list of core features proposed for reporting in SCD studies is provided, which will enable comparability of research across different settings. Finally, a set of features is presented, which in accordance with current knowledge, increases the likelihood of the presence of preclinical AD in individuals with SCD. This list is referred to as SCD plus.

Outcome over seven years of healthy adults with and without subjective cognitive impairment

Subjective cognitive impairment (SCI) in older persons without manifest symptomatology is a common condition with a largely unclear prognosis. We hypothesized that (1) examining outcome for a sufficient period by using conversion to mild cognitive impairment (MCI) or dementia would clarify SCI prognosis, and (2) with the aforementioned procedures, the prognosis of SCI subjects would differ significantly from that of demographically matched healthy subjects, free of SCI, termed no cognitive impairment (NCI) subjects.

The Frontal Lobes, Epilepsy, and Behavior

The frontal lobes have been overshadowed by the temporal lobes in the vast literature addressing the neurobehavioral and psychological perspectives of epilepsy. The purpose of this review is to summarize contemporary anatomicobehavioral correlations and to highlight the frontal lobe contributions to the neurology, neuropsychology, and neuropsychiatry of epilepsy, in general, and to temporal lobe epilepsy (TLE) and frontal lobe epilepsy (FLE), in particular. Much evidence has accumulated suggesting that focal epileptogenic tissue may have effects on distant neural systems. Data supporting the case that the frontal regions are preferentially affected in TLE are presented. Emphasis is placed on the results of numerous functional imaging studies demonstrating correlations between frontal hypoperfusion and cognitive or mood impairments in patients with TLE.

The BEHAVE-AD Assessment System: A Perspective, A Commentary on New Findings, and A Historical Review

Background: Behavioral and psychological symptoms of dementia (BPSD) and associated disturbances in Alzheimers disease (AD) are a source of distress and burden for spouses, professional caregivers, and others with responsibilities for the care of individuals with AD. BPSD with behavioral disturbances are also associated with more rapid institutionalization and increased morbidity and mortality for persons with AD. Objectives: In this review and commentary, we discuss the history of the development of BPSD and behavioral disturbance assessments, which are distinct from those evaluating cognitive and functional symptoms of AD. In particular, we review the informant-based Behavioral Pathology in Alzheimers Disease Rating Scale (BEHAVE-AD), the related, potentially more sensitive, BEHAVE-AD Frequency-Weighted Severity Scale (BEHAVE-AD-FW), and the direct subject evaluation-based Empirical BEHAVE-AD Rating Scale (E-BEHAVE-AD). The kinds of medications that alleviate behavioral symptoms on these measures as well as the problems and possibilities for further advances with these medications are discussed. Finally, the importance of distinguishing BPSD and behavioral disturbance remediation in AD from the treatment of cognitive decline and other aspects of AD is emphasized in the context of appropriate assessment methodology. The objective of this paper is to provide a framework for further advances in the treatment of BPSD and associated behavioral disturbances in AD and, consequently, a framework for continuing improvements in the lives of individuals with AD and those who share the burden of the disease with the AD person.

The clinical applications of EEG: origins

The first paper in our series Classics in Epilepsy and Behavior is ‘‘Epilepsy: A Paroxysmal Cerebral Dysrhythmia,’’ published in Brain by Gibbs, Gibbs, and Lennox in 1937. The paper serves as a landmark for spurring interest in the role of EEG in clinical epilepsy as well as linking the term ‘‘psychomotor epilepsy’’ to a specific EEG pattern. The application of EEG technology to human seizure disorders was slow. Richard Caton (1842–1926), a British physician, published his findings of the electrical phenomena of the exposed cerebral hemispheres of rabbits and monkeys in 1875. According to Brazier, the discovery of the EEG went unnoticed by clinicians in Western Europe and America for nearly 60 years [1]. However, work proceeded in Eastern Europe with the ‘‘rediscovery’’ of EEG by Adolf Beck (1863–1942) in Krakow, Poland, in 1891 and the tests of whether an epileptic attack might be accompanied by abnormal EEG activity in dogs by Pavel Yurevich Kaufman (1877–1951) in St. Petersburg in 1912. Gibbs, Gibbs, and Lennox thank ‘‘the pioneer work of Berger’’ in developing the EEG [2]. Indeed, Hans Berger (1873–1941), a German neuropsychiatrist, began study of the human EEG in 1924 in patients with large skull defects (post-World War I injuries), but soon recognized that readings could be made just as well through an intact skull and scalp [3]. A complex character, Berger worked in isolation with incredibly primitive equipment. The first report of 1929 recorded from the head of Berger s son featured the alpha rhythm and the alpha blocking response [4]. Berger s findings were greeted with universal skepticism, but they were eventually confirmed in 1934 by Adrian and Matthews in England [5]. While documenting the first recordings of the EEG in epilepsy, Berger failed to recognize the clinical significance of EEG to seizure disorders. Brazier explains this oversight as counter to Berger s conception of EEG as a means to study the nature of mental energy (‘‘psychische Energie’’) [1]. More a ‘‘psychophysiologist’’ than a neurophysiologist, Berger sought the correlate of mental energy in EEG. Formidable technological gaps contributed to the slow incorporation of EEG to human seizure disorders; however, conceptual gaps regarding the nature and interpretation of brain waves remained even more significant obstacles. America played no role in the early development of experimental EEG [3]. Instead, a small group of American neurophysiologists of the late 1920s deemed themselves ‘‘axonologists’’ and focused their efforts on separating the components of conducted action potentials in somatic and autonomic nerves [6]. As Gibbs recalled in an interview, ‘‘the axonologists whittled the nervous system down to one axon and knocked themselves out studying that. They told me that studying the whole brain (i.e., EEG) was just ridiculous’’ [7]. Hallowell Davis (1896–1992) and colleagues at Harvard Medical School confirmed Berger s alpha rhythm in late 1934 [8]. This demonstration lured Frederic and Erna Gibbs to join forces with him and try the ‘‘brainwave’’ equipment as a potential means of studying epilepsy [8]. Frederic Gibbs (1903–1992) had come from Johns Hopkins University to work with William G. Lennox (1884–1960), already a well-known epileptologist, at Boston City Hospital. Lennox and Gibbs had been frustrated in their work on a circulatory hypothesis of seizures. They demonstrated no cerebral anoxia with seizures; however, their techniques remain pioneer work in cerebral blood flow studies [3]. Erna L. Gibbs, an immigrant from Germany, was originally a technical coworker of Lennox, married Frederic Gibbs, and was one of the world s first EEG technicians and co-author of many papers and texts. Epilepsy & Behavior 3 (2002) 393–394

Commentary on ''A roadmap for the prevention of dementia II: Leon Thal Symposium 2008.'' Subjective cognitive impairment as an antecedent of Alzheimer's dementia: Policy import

It is becoming increasingly evident that the process of Alzheimer’s disease (AD), which is known to be gradual and continuous, begins many years, indeed, decades before symptoms of dementia become evident. Dementia is defined as a condition in which the cognitive deficits must be sufficiently severe to cause impairment in occupational and social functioning [1]. The physiologic mechanisms eventuating in dementia and AD may begin very early in life [2–4]. Similarly, pathologic hallmarks of AD appear to develop decades before the dementia of AD becomes manifest. For example, Braak and Braak report that in a consecutive series of 2,369 unselected autopsy cases, approximately 50% of subjects who died between age 50 and 55 manifested the neurofibrillary pathology of AD [5]. In terms of the behaviorally manifest process of the development and course of AD, more than two decades ago, we described seven major stages in the evolution of the brain aging and progressive dementia process of AD. These descriptions, in the form of the Global Deterioration Scale (GDS) [6] and related measures [7,8], had an immediate impact on the medical community [9] and lay-persons [10], as well as the research community. However, the meaning and implications of these stages for the medical and scientific communities and for the research agenda are continuing to evolve, and, in fact, are acquiring a new sense of urgency. One of the stages described in the GDS, stage 3, is a stage prior to the development of overt dementia, in which deficits become subtly evident, for example in the context of a detailed clinical interview or in demanding employment settings. In 1988 we published cross-sectional findings, which indicated diverse deficits in psychometric test performance for persons at this GDS 3 stage, in comparison with that of persons in earlier stages [11]. On the basis of these findings, we suggested the terminology “mild cognitive impairment,” to describe persons at this GDS 3 stage [11]. Subsequently, in longitudinal studies: (1) we verified the relative morbidity of the GDS 3 stage of mild cognitive impairment (MCI) in comparison with earlier stages [12], and (2) we prospectively confirmed earlier estimates [13] that this stage of MCI lasts approximately 7 years in otherwise healthy older persons prior to the advent of overt dementia pathology [14]. Changes in MCI subjects in comparison with both persons at earlier GDS stages and in comparison with persons with mild or more severe dementia in terms of diverse aspects, including motor changes, neurologic reflex changes, and diverse neuroimaging assessments, were extensively described in the literature (see Reisberg, et al., 2008 [15], for a review). In recent years, Petersen and colleagues have somewhat modified our descriptions of MCI and, working with various groups, enhanced the recognition and worldwide understanding of this pre-dementia condition [16–19]. As a prodromal, identifiable condition, prior to the advent of the overt dementia of AD, the recognition of MCI greatly extends the epidemiologic, social, and economic dimensions of the evolving pathology of AD. The GDS also identifies a stage prior to MCI in which older persons develop subjective complaints of cognitive impairment (SCI, GDS stage 2). More than two decades ago, we hypothesized that this SCI stage precedes MCI in the course of the development of AD, and lasts approximately 15 years before MCI symptoms become manifest [13]. Because the mild cognitive impairment stage lasts ~ 7 years prior to mild AD, an understanding and recognition of the nature and import of MCI was essential before the SCI stage could be elucidated. Recent studies are identifying physiologic differences between SCI subjects and age-matched no cognitive impairment [NCI] (GDS stage 1) persons in physiologic parameters including brain metabolism [20] and cortisol levels [21]. Prognostic markers of the development of subsequent mild cognitive impairment in persons with SCI are also being identified, for example using electrophysiologic markers [22]. These studies have supported the earlier estimates of the duration of the SCI stage as being approximately 15 years prior to the advent of MCI [13,22,23]. Importantly, current studies are also showing evidence of quantifiable cognitive deficits accompanying these SCI symptoms. For example, subjects with SCI were recently observed to score more than a half-point lower on average on the mini-mental status examination [24], than an NCI cohort [25]. However, the SCI subjects, despite poorer cognitive performance on average than similarly aged NCI persons, continue to score well within the normal range on psychological and other test measures. Consequently, the import for society of the observable performance decrements in this pre-MCI stage, for example in terms of decreased occupational performance, if any, remains to be determined. It is clear from current epidemiologic studies that SCI symptoms become very common as persons age. These symptoms occur in approximately a quarter to a half of all persons in the community aged 65 or greater [26–29]. It is also clear that these SCI symptoms are very troubling to many older persons. Over the past 30 years, approximately a third of persons presenting to our aging and dementia research center have come because of these SCI symptoms. Also, these subjective complaints of impairment appear to be a major reason for older persons taking a variety of prescription and non-prescription treatments, including off-label medications approved for dementia, or other conditions, and non-prescription vitamins and nutraceuticals [30]. Hence, the economic consequences of the SCI symptoms in many older persons are clearly large in terms of societal costs.

Comprehensive, Individualized, Person-Centered Management of Community-Residing Persons with Moderate-to-Severe Alzheimer Disease: A Randomized Controlled Trial.

Background/Aims: The aim was to examine added benefits of a Comprehensive, Individualized, Person-Centered Management (CI-PCM) program to memantine treatment. Methods: This was a 28-week, clinician-blinded, randomized, controlled, parallel-group study, with a similar study population, similar eligibility criteria, and a similar design to the memantine pivotal trial of Reisberg et al. [N Engl J Med 2003;348:1333-1341]. Twenty eligible community-residing Alzheimer disease (AD) subject-caregiver dyads were randomized to the CI-PCM program (n = 10) or to usual community care (n = 10). Primary outcomes were the New York University Clinicians Interview-Based Impression of Change Plus Caregiver Input (NYU-CIBIC-Plus), assessed by one clinician set, and an activities of daily living inventory, assessed by a separate clinician set at baseline and at weeks 4, 12, and 28. Results: Primary outcomes showed significant benefits of the CI-PCM program at all post-baseline evaluations. Improvement on the NYU-CIBIC-Plus in the management group at 28 weeks was 2.9 points over the comparator group. The memantine 2003 trial showed an improvement of 0.3 points on this global measure in memantine-treated versus placebo-randomized subjects at 28 weeks. Hence, globally, the management program intervention benefits were 967% greater than memantine treatment alone. Conclusion: These results are approximately 10 times those usually observed with both nonpharmacological and pharmacological treatments and indicate substantial benefits with the management program for advanced AD persons.

Imaging Alzheimer's Disease: The Evolution of Biomarkers

Tomographic imaging is about 40 years old and has made considerable progress with the early and differential diagnosis of Alzheimer’s disease (AD). In this summary, we classified the imaging in AD into three major categories: (1) general descriptive markers of brain damage, which can be either based on structural or functional imaging data; (2) sensitive early predictive markers that are useful to recognize problems but are not useful for the differential diagnosis as they are not specific for AD or for types of pathology by which AD is recognized; and (3) pathology-specific imaging tests that target specific abnormal proteins such as amyloid beta or neurofibrillary pathology (tau). The evolution of imaging technology in all three areas has contributed to the improved characterization of disease risk and has enabled the terminology and the clinic to diagnose mild cognitive impairment and even earlier preclinical states. As our understanding of the evolution of AD has improved, so has our need for additional imaging markers such markers for brain inflammation. Further, the capacity to predict with increasing early accuracy the symptoms of neurodegenerative diseases has called into question the ethical basis for communication of results, especially when treatments are not available. Today we are at the most important step of multifactorial risk assessment in minimally affected individuals, the discovery of disease mechanisms, and early therapeutic intervention.

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Prediction of cognitive decline in normal older persons without subjective cognitive impairment: A seven year longitudinal study

Background: Recent studies have characterized a pre-Mild Cognitive Impairment (MCI), Subjective Cognitive Impairment (SCI) stage in the aging and dementia continuum beginning w 20 years prior to the onset of dementia in Alzheimer’s disease (AD) (Reisberg, et al., Alzheimer’s & Dementia, 2008; Reisberg and Gauthier, International Psychogeriatrics, 2008). It appears that predictors of SCI, in addition to overt cognitive decline, in normal older persons free of subjective complaints (No Cognitive Impairment [NCI]), have not previously been examined longitudinally. Methods: A consecutive series of healthy older persons with NCI, 40 years of age, was studied extensively at baseline and followed longitudinally over an 18 year study interval. Outcome was defined dichotomously as: (1) decline to a diagnosis of SCI, MCI, or dementia, or (2) absence of decline over the follow-up interval. Baseline predictors of subsequent decline were examined. Results: 0f 60 healthy subjects with no cognitive impairment (NCI) seen at baseline, 47 subjects (78.3%) were followed over a mean of 6.763.1 years. Baseline characteristics of subjects followed (means6SDs), included: age, 64.168.9 years; education, 16.162.4 years; and MMSE, 29.660.8. The majority of subjects, 55%, were women. At the last period of observation, 10 subjects remained NCI, and 37 subjects declined. Of the decliners, 29 (78.4%) had SCI at the last observation, 7 (18.9%) had MCI, and 1 subject (2.7%) had AD. Significant baseline predictors of decline included age (p<0.01), and psychometric baseline scores on paragraphs initial recall, the digit symbol substitution test, WAIS digits forward, and a combinatorial psychometric measure (p < 0.05). In a logistic regression analysis, which controlled for baseline demographic variables (i.e., age, gender, and education) and follow-up time, three baseline variables contributed significantly to the probability of decline: paragraphs initial recall (p1⁄40.028), WAIS digits forward (p1⁄40.018), and the combinatorial psychometric deterioration score (p1⁄40.050). Conclusions: Apart from age, overall psychometric test performance, and specific psychometric test variables, can predict decline in cognitively normal, healthy older persons who are free of Subjective Cognitive Impairment. These findings are of relevance for future treatment trials directed towards AD prevention more than 20 years prior to the advent of overt dementia.