Now is the Time to Improve Cognitive Screening and Assessment for Clinical and Research Advancement.

Wang et al. analyze Mini-Mental State Examination (MMSE) and Montreal Cognitive Assessment accuracy as screening tests for detecting dementia associated with Alzheimer's disease (AD). Such tests are at the center of controversy regarding recognition and treatment of AD. The continued widespread use of tools such as MMSE (1975) underscores the failure of advancing cognitive screening and assessment, which has hampered the development and evaluation of AD treatments. It is time to employ readily available, efficient computerized measures for population/mass screening, clinical assessment of dementia progression, and accurate determination of approaches for prevention and treatment of AD and related conditions.

Reduced rank multinomial logistic regression in Markov chains with application to cognitive data.

Finite Markov chains are useful tools for studying transitions among health states; these chains can be complex consisting of a mix of transient and absorbing states. The transition probabilities, which are often affected by covariates, can be difficult to estimate due to the presence of many covariates and/or a subset of transitions that are rarely observed. The purpose of this article is to show how to estimate the effect of a subset of covariates of interest after adjusting for the presence of multiple other covariates by applying multidimensional dimension reduction to the latter. The case in which transitions within each row of the one-step transition probability matrix are estimated by multinomial logistic regression is discussed in detail. Dimension reduction for the adjustment covariates involves estimating the effect of the covariates by a product of matrices iteratively; at each iteration one matrix in the product is fixed while the second is estimated using either standard software or nonlinear estimation, depending on which of the matrices in the product is fixed. The algorithm is illustrated by an application where the effect of at least one Apolipoprotein-E (APOE) gene ϵ4 allele on transition probability is estimated in a Markov Chain that includes adjustment for eight covariates and focuses on transitions from normal cognition to several forms of mild cognitive impairment, with possible absorption into dementia. Data were drawn from annual cognitive assessments of 649 participants enrolled in the BRAiNS cohort at the University of Kentucky's Alzheimer's Disease Research Center.

Longitudinal assessment of dementia measures in Down syndrome.

INTRODUCTION: Early detection of dementia symptoms is critical in Down syndrome (DS) but complicated by clinical assessment barriers. The current study aimed to characterize cognitive and behavioral impairment using longitudinal trajectories comparing several measures of cognitive and behavioral functioning. METHODS: Measures included global cognitive status (Severe Impairment Battery [SIB]), motor praxis (Brief Praxis Test [BPT]), and clinical dementia informant ratings (Dementia Questionnaire for People with Learning Disabilities [DLD]). One-year reliability was assessed using a two-way mixed effect, consistency, single measurement intraclass correlation among non-demented participants. Longitudinal assessment of SIB, BPT, and DLD was completed using linear mixed effect models. RESULTS: One-year reliability (n = 52; 21 male) was moderate for DLD (0.69 to 0.75) and good for SIB (0.87) and BPT (0.80). Longitudinal analysis (n = 72) revealed significant age by diagnosis interactions for SIB (F(2, 115.02) = 6.06, P = .003), BPT (F(2, 85.59) = 4.56, P = .013), and DLD (F(2, 103.56) = 4.48, P = .014). SIB progression (PR) had a faster decline in performance versus no-dementia (ND) (t(159) = -2.87; P = .013). Dementia had a faster decline in BPT performance versus ND (t(112) = -2.46; P = .041). PR showed quickly progressing scores compared to ND (t(128) = -2.86; P = .014). DISCUSSION: Current measures demonstrated moderate to good reliability. Longitudinal analysis revealed that SIB, BPT, and DLD changed with age depending on diagnostic progression; no change rates were dependent on baseline cognition, indicating usefulness across a variety of severity levels in DS.

Convergent and discriminant validity of the Immediate Postconcussion Assessment and Cognitive Testing Battery (ImPACT) in young athletes.

Sports concussions are recognized as significant injuries among young athletes. Research demonstrates that return-to-play prior to becoming asymptomatic has significant repercussions including sustained cognitive deficits. Many programs have begun to use computerized testing rather than traditional neuropsychological tests to (a) determine baseline performance, (b) track symptoms, and (c) measure symptoms following concussion. Immediate Post-Concussion Assessment and Cognitive Testing (ImPACT) is one such tool. The current study examined ImPACT's convergent and discriminant validity by comparing scores from sports-related concussion athletes (SRC) to those from nonconcussed controls (CTL). SRC included 29 athletes, ages 12-16, referred for neuropsychological assessment following sports-related concussions. CTL included 25 healthy athletes, ages 12-16, who were concussion-free in the past year. Overall, results showed general support for ImPACT, when used to screen cognition. In fact, all ImPACT domains successfully differentiated between SRC and CTL athletes. Evidence supporting appropriate convergent validity was best for the Visual Memory domain. Further, ImPACT domains demonstrated variable discriminant validity. Overall examination of validity demonstrated that ImPACT has some weaknesses but may have utility in detecting postconcussion cognitive impairment.

Self-reported head injury and risk of late-life impairment and AD pathology in an AD center cohort.

AIMS: To evaluate the relationship between self-reported head injury and cognitive impairment, dementia, mortality, and Alzheimer's disease (AD)-type pathological changes. METHODS: Clinical and neuropathological data from participants enrolled in a longitudinal study of aging and cognition (n = 649) were analyzed to assess the chronic effects of self-reported head injury. RESULTS: The effect of self-reported head injury on the clinical state depended on the age at assessment: for a 1-year increase in age, the OR for the transition to clinical mild cognitive impairment (MCI) at the next visit for participants with a history of head injury was 1.21 and 1.34 for the transition from MCI to dementia. Without respect to age, head injury increased the odds of mortality (OR = 1.54). Moreover, it increased the odds of a pathological diagnosis of AD for men (OR = 1.47) but not women (OR = 1.18). Men with a head injury had higher mean amyloid plaque counts in the neocortex and entorhinal cortex than men without. CONCLUSIONS: Self-reported head injury is associated with earlier onset, increased risk of cognitive impairment and dementia, increased risk of mortality, and AD-type pathological changes.

Adjusting for mortality when identifying risk factors for transitions to mild cognitive impairment and dementia.

Risk factors for mild cognitive impairment (MCI) and dementia are often investigated without accounting for the competing risk of mortality, which can bias results and lead to spurious conclusions, particularly regarding protective factors. Here, we apply a semi-Markov modeling approach to 531 participants in the University of Kentucky Biologically Resilient Adults in Neurological Studies (BRAiNS) longitudinal cohort, over one-third of whom died without transitioning to a cognitively impaired clinical state. A semi-Markov approach enables a statistical study of clinical state transitions while accounting for the competing risk of death and facilitates insights into both the odds that a risk factor will affect clinical transitions as well as the age at which the transition to MCI or dementia will occur. Risk factors assessed in the current study were identified by matching those reported in the literature with the data elements collected on participants. The presence of Type II diabetes at baseline shortens the time it takes cognitively intact individuals to transition to MCI by seven years on average while use of estrogen replacement therapy at enrollment (baseline) decreases the time required to convert from MCI to dementia by 1.5 years. Finally, smoking and being overweight do not promote transitions to impaired states but instead hasten death without a dementia. In contrast, conventional statistical analyses based on Cox proportional hazards models fail to recognize diabetes as a risk, show that being overweight increases the risk of clinical MCI, and that high blood pressure at baseline increases the risk of a dementia.

Improving dementia care: the role of screening and detection of cognitive impairment.

The value of screening for cognitive impairment, including dementia and Alzheimer's disease, has been debated for decades. Recent research on causes of and treatments for cognitive impairment has converged to challenge previous thinking about screening for cognitive impairment. Consequently, changes have occurred in health care policies and priorities, including the establishment of the annual wellness visit, which requires detection of any cognitive impairment for Medicare enrollees. In response to these changes, the Alzheimer's Foundation of America and the Alzheimer's Drug Discovery Foundation convened a workgroup to review evidence for screening implementation and to evaluate the implications of routine dementia detection for health care redesign. The primary domains reviewed were consideration of the benefits, harms, and impact of cognitive screening on health care quality. In conference, the workgroup developed 10 recommendations for realizing the national policy goals of early detection as the first step in improving clinical care and ensuring proactive, patient-centered management of dementia.

Digital pathology and image analysis for robust high-throughput quantitative assessment of Alzheimer disease neuropathologic changes.

Quantitative neuropathologic methods provide information that is important for both research and clinical applications. The technologic advancement of digital pathology and image analysis offers new solutions to enable valid quantification of pathologic severity that is reproducible between raters regardless of experience. Using an Aperio ScanScope XT and its accompanying image analysis software, we designed algorithms for quantitation of amyloid and tau pathologies on 65 ß-amyloid (6F/3D antibody) and 48 phospho-tau (PHF-1)-immunostained sections of human temporal neocortex. Quantitative digital pathologic data were compared with manual pathology counts. There were excellent correlations between manually counted and digitally analyzed neuropathologic parameters (R² = 0.56-0.72). Data were highly reproducible among 3 participants with varying degrees of expertise in neuropathology (intraclass correlation coefficient values, >0.910). Digital quantification also provided additional parameters, including average plaque area, which shows statistically significant differences when samples are stratified according to apolipoprotein E allele status (average plaque area, 380.9 µm² in apolipoprotein E [Latin Small Letter Open E]4 carriers vs 274.4 µm² for noncarriers; p < 0.001). Thus, digital pathology offers a rigorous and reproducible method for quantifying Alzheimer disease neuropathologic changes and may provide additional insights into morphologic characteristics that were previously more challenging to assess because of technical limitations.

Lewy body pathology in normal elderly subjects.

Lewy bodies and Lewy neurites are the hallmark neuropathologic findings in Parkinson disease, Parkinson disease with dementia, dementia with Lewy bodies, and other alpha-synucleinopathies. They have also been described in the brains of normal older individuals and referred to as incidental Lewy body disease. The purpose of this study was to determine the prevalence of Lewy bodies and Lewy neurites (Lewy body pathology [LBP]) in 139 autopsies from our normal volunteer control group of the University of Kentucky Alzheimer's Disease Center. All subjects were followed longitudinally and were cognitively normal and without any type of movement disorder, neuropsychiatric features, or other CNS findings. The brains of 33 of 139 normal subjects contained LBP in various regions. The most common regions involved were the medulla (26%), amygdala (24%), pons (20%), and midbrain (20%). No mean statistical differences were found between those with and without LBP on any demographic or cognitive variable, Braak stage, or neurofibrillary tangle and neuritic plaque quantitation. An explanation for the high prevalence of LBP in our elderly, well-educated study group is not clear, although it does not seem to be related to aging or the presence of Alzheimer disease pathology. Overall, our findings support the concept that incidental Lewy body disease most likely represents preclinical or presymptomatic Parkinson disease, Parkinson disease with dementia, or dementia with Lewy bodies.

Cost-effectiveness of memantine in moderate-to-severe Alzheimer's disease patients receiving donepezil.

OBJECTIVE: The efficacy and safety of memantine in patients with moderate-to-severe Alzheimer's disease (AD) receiving stable doses of donepezil were recently demonstrated in a phase III trial. The cost-effectiveness of such therapy is unknown. RESEARCH DESIGN AND METHODS: A microsimulation model was developed to depict AD progression over time and associated clinical and economic outcomes. AD progression was measured in terms of decline in cognitive function, as assessed by the Severe Impairment Battery (SIB). At model entry, patients were assumed to have moderate-to-severe AD, to be on stable doses of donepezil, and to begin combination therapy with memantine, or continue to receive donepezil alone; duration of therapy was assumed to be 1 year. Drug efficacy was based on data from a phase III trial. Key assumptions of the model included: (1) efficacy of study drugs would extend to 1 year; (2) measures of cognitive function could be mapped to one another, as well as to global measures of disease severity; and (3) following therapy discontinuation, cognitive function would revert immediately to natural history levels. Cost-effectiveness was assessed in terms of cost (2005 US$) per quality-adjusted life-year (QALY) gained over a lifetime (3% discount rate). RESULTS: SIB scores were estimated to improve by 3.3 over 1 year from therapy with memantine plus donepezil (vs. donepezil alone). While pharmacotherapy costs were estimated to increase by $1250 during the year of memantine treatment, costs of formal and informal services were estimated to decrease by $1240 over this period and by $1493 (discounted present value) over a lifetime. Findings were sensitive to the assumed SIB score at therapy initiation; cost-effectiveness was better for patients with higher initial SIB scores (i.e., less severe disease). CONCLUSION: In patients with moderate-to-severe AD already receiving donepezil, treatment with memantine results in improved clinical outcomes and reduced total costs of care.

Shared random effects analysis of multi-state Markov models: application to a longitudinal study of transitions to dementia.

Multi-state models are appealing tools for analysing data about the progression of a disease over time. In this paper, we consider a multi-state Markov chain with two competing absorbing states: dementia and death and three transient non-demented states: cognitively normal, amnestic mild cognitive impairment (amnestic MCI), and non-amnestic mild cognitive impairment (non-amnestic MCI). The likelihood function for the data is derived and estimates for the effects of the covariates on transitions are determined when the process can be viewed as a polytomous logistic regression model with shared random effects. The presence of a shared random effect not only complicates the formulation of the likelihood but also its evaluation and maximization. Three approaches for maximizing the likelihood are compared using a simulation study; the first method is based on the Gauss-quadrature technique, the second method is based on importance sampling ideas, and the third method is based on an expansion by Taylor series. The best approach is illustrated using a longitudinal study on a cohort of cognitively normal subjects, followed annually for conversion to mild cognitive impairment (MCI) and/or dementia, conducted at the Sanders Brown Center on Aging at the University of Kentucky.

A systematic review of assessment and treatment of moderate to severe Alzheimer's disease.

OBJECTIVE: The systematic, large-scale study of therapies for moderate to severe Alzheimer's disease (AD) is a relatively recent advancement in the field. This review describes for the general practitioner the characterization of moderate to severe AD, discusses the development of metrics sensitive to the constellation of symptoms in these patients, and critically evaluates the use of those measures in moderate to severe AD clinical trials. DATA SOURCES: Published clinical trials obtained by MEDLINE searches used the following key words: moderate AD, severe AD, donepezil, rivastigmine, galantamine, memantine, and anti-dementia agents. Clinical trials were limited by language (English), study type (clinical trial), and publication dates (1990-2005). STUDY SELECTION: Nine clinical trials comprise the studies conducted to date in moderate to severe AD and include 5 prospective randomized clinical trials (3 for memantine, 2 for donepezil) and 4 retrospective subanalyses (2 for galantamine, 2 for rivastigmine) of primary datasets. DATA EXTRACTION: Clinical trials are summarized and major findings are reviewed. DATA SYNTHESIS: The data reviewed support the decision to initiate and maintain treatment in moderate to severe AD patients. CONCLUSIONS: The development and implementation of improved metrics for moderate to severe AD patients has revealed that meaningful benefits are attainable in this patient population by treatment with the N-methyl-D-aspartate receptor antagonist memantine. Evidence also indicates a benefit from cholinesterase inhibitor treatment, although further study of these agents in this patient population is warranted.

The emotional ramifications of unmet need in dementia caregiving.

Using a unique measure of unmet need that taps into several dimensions of informal long-term care, the present study included data from 694 informal caregivers of persons suffering from dementia at different times in the caregiving career (e.g., at home, following institutionalization, following the death of the care recipient). Multivariate regression models found that unmet need for either confidante or formal support had key implications for caregivers' emotional distress in each of the care situations. The findings suggest that conceptual models should incorporate unmet need as a viable predictor of caregiving outcomes and that assessment of unmet need may provide guidance in the development of more refined psychosocial and community-based intervention protocols.