Evaluation of an 8-item Severe Impairment Battery (SIB-8) vs. the full SIB in moderate to severe Alzheimer's disease patients participating in a donepezil study.

AIM: The Severe Impairment Battery (SIB), a reliable cognitive measure for evaluating treatment response in advanced Alzheimer's disease (AD), takes approximately 20 min to administer. A recently derived 8-item version of the SIB - the SIB-8 - which takes about 3 min to administer, may represent a more convenient tool for use in clinical practice. The current analyses further explored the SIB-8 scale with respect to its validity and sensitivity. METHODS: A post hoc analysis was performed using data from a 24-week trial of donepezil 23 mg/day and 10 mg/day in > 1400 patients with moderate to severe AD [baseline Mini-Mental State Examination (MMSE) score 0-20]. Treatment effects on cognition (patterns of score change) were assessed using the full SIB and SIB-8 in the total study population and subgroups based on concomitant memantine use and baseline MMSE. Internal consistency/agreement and correlations between the SIB and SIB-8 and other clinical end points were evaluated. RESULTS: Assessment of score changes from baseline to week 24 with donepezil (23 or 10 mg/day) demonstrated comparable patterns of change when using the SIB-8 and the full SIB, despite inherent differences in the total score ranges for the two scales. Internal consistency/agreement between the full SIB and SIB-8 was good (Cronbach's alphas: 0.77-0.95). SIB-8 scores reliably correlated with SIB total scores (r = 0.859, baseline; r = 0.900, week 24; p < 0.0001), as well as MMSE scores (r = 0.7163, baseline; r = 0.7963, week 24; p < 0.0001). Scores on both SIB scales were moderately associated with functional measures at baseline and week 24. CONCLUSIONS: In this post hoc analysis, similar treatment effects were measured by the full SIB and the SIB-8. Very good internal consistency/agreement and strong correlations between the SIB and the more rapid and convenient SIB-8 indicate that the SIB-8 may be a useful and efficient clinical proxy for the full SIB in evaluating treatment response in patients with advanced AD.

Novel white matter tract integrity metrics sensitive to Alzheimer disease progression.

BACKGROUND AND PURPOSE: Along with cortical abnormalities, white matter microstructural changes such as axonal loss and myelin breakdown are implicated in the pathogenesis of Alzheimer disease. Recently, a white matter model was introduced that relates non-Gaussian diffusional kurtosis imaging metrics to characteristics of white matter tract integrity, including the axonal water fraction, the intra-axonal diffusivity, and the extra-axonal axial and radial diffusivities. MATERIALS AND METHODS: This study reports these white matter tract integrity metrics in subjects with amnestic mild cognitive impairment (n = 12), Alzheimer disease (n = 14), and age-matched healthy controls (n = 15) in an effort to investigate their sensitivity, diagnostic accuracy, and associations with white matter changes through the course of Alzheimer disease. RESULTS: With tract-based spatial statistics and region-of-interest analyses, increased diffusivity in the extra-axonal space (extra-axonal axial and radial diffusivities) in several white matter tracts sensitively and accurately discriminated healthy controls from those with amnestic mild cognitive impairment (area under the receiver operating characteristic curve = 0.82-0.95), while widespread decreased axonal water fraction discriminated amnestic mild cognitive impairment from Alzheimer disease (area under the receiver operating characteristic curve = 0.84). Additionally, these white matter tract integrity metrics in the body of the corpus callosum were strongly correlated with processing speed in amnestic mild cognitive impairment (r = |0.80-0.82|, P < .001). CONCLUSIONS: These findings have implications for the course and spatial progression of white matter degeneration in Alzheimer disease, suggest the mechanisms by which these changes occur, and demonstrate the viability of these white matter tract integrity metrics as potential neuroimaging biomarkers of the earliest stages of Alzheimer disease and disease progression.

Effect of tramiprosate in patients with mild-to-moderate Alzheimer's disease: exploratory analyses of the MRI sub-group of the Alphase study.

OBJECTIVES: The efficacy, safety and disease-modification of tramiprosate (homotaurine)were investigated in a recently completed large-scale Phase III clinical study in patients with mild to moderate Alzheimer's disease (AD), the Alphase study. Disease-modification was assessed using longitudinal volumetric MRI (vMRI) measurements of the hippocampus in a subgroup of patients. The present study describes the vMRI, cognitive and clinical results obtained in this subgroup. DESIGN: Multi-center, double-blind, randomized, placebo-controlled study in a subset of the 1052 patients of the Alphase study. SETTING: 51 vMRI investigative sites in the United States and Canada. PARTICIPANTS: A total of 508 patients underwent vMRI scanning. Of these, 312 provided scan pairs for assessing hippocampus volume changes and were included in the analyses. INTERVENTIONS: Patients were randomized to receive Placebo BID (n = 109), tramiprosate 100 mg BID (n = 103), or tramiprosate 150 mg BID (n = 100) for 78 weeks. MEASUREMENTS: Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-cog) and Clinical Dementia Rating-Sum-of-boxes CDR-SB assessments were conducted at Baseline and at Weeks 13, 26, 39, 52, 65 and 78. Exploratory analyses were performed using similar First and Final mixed-effects repeated-measures models that were used for the analysis of the entire patient dataset. RESULTS: Psychometric score results showed numerical trends in favour of tramiprosate that did not reach statistical significance. While there were no statistically significant group differences in hippocampus volume using the First modeling approach, a significant dose-response reduction in hippocampus volume change was found in the Final models. Moreover, there was a marginally significant overall treatment main effect and a significant slope difference in favour of tramiprosate according to the Final model analysis of the ADAS-cog scores. ADAS-cog scores analyzed according to this model also revealed differences in favor of the tramiprosate 150 mg group at weeks 26 and 52, with marginally significant differences at Weeks 13 and 39. Slope analyses of ADAS-cog score changes showed significant differences in favor of the 150 mg BID group, and when both active groups were combined, in comparison to the placebo group. No between-group differences with respect to changes to each visit in the CDR-SB were observed with either modeling approach. Although there was a similar dose-response relationship observed in the hippocampus volume and ADAS-cog Final model analyses, the overall changes in psychometric scores and hippocampus volume were not significantly correlated. CONCLUSION: Exploratory analysis of the vMRI subgroup suggests that tramiprosate slows hippocampal atrophy, and reveals some evidence of a beneficial effect on cognition. The clinical validity of the vMRI biomarker is discussed.

Donepezil treatment of patients with MCI: a 48-week randomized, placebo-controlled trial.

BACKGROUND: Treatment of mild cognitive impairment (MCI) with cholinesterase inhibitors may improve symptoms. METHODS: In this multicenter, randomized, placebo-controlled trial, subjects with MCI entered a 3-week placebo run-in period followed by 48 weeks of double-blind donepezil (5 mg/day for 6 weeks, then 10 mg/day for 42 weeks) or placebo treatment. Primary efficacy variables included change from baseline in the modified Alzheimer Disease Assessment Scale-cognitive subscale (ADAS-Cog) and Clinical Dementia Rating Scale-sum of boxes (CDR-SB) after 48 weeks of treatment (modified intention-to-treat analysis). Secondary efficacy measures evaluated cognition, behavior, and function. RESULTS: The dual primary efficacy endpoint was not reached. We noted a small, but significant, decrease in modified ADAS-Cog scores in favor of donepezil at study endpoint. Little change from baseline in CDR-SB and secondary variables was observed for either group. Patient Global Assessment scores favored donepezil at all time points except week 12 (p < or = 0.05). Perceived Deficits Questionnaire scores favored donepezil at week 24 (p = 0.05). Clinical Global Impression of Change-MCI scores favored donepezil only at week 6 (p = 0.04). Adverse events were generally mild or moderate. More donepezil-treated subjects (18.4%) discontinued treatment due to adverse events than placebo-treated subjects (8.3%). CONCLUSIONS: Donepezil demonstrated small but significant improvement on the primary measure of cognition but there was no change on the primary measure of global function. Most other measures of global impairment, cognition, and function were not improved, possibly because these measures are insensitive to change in MCI. Responses on subjective measures suggest subjects perceived benefits with donepezil treatment.

Prediction of longitudinal cognitive decline in normal elderly with subjective complaints using electrophysiological imaging.

An extensive literature reports changes in quantitative electroencephalogram (QEEG) with aging and a relationship between magnitude of changes and degree of clinical deterioration in progressive dementia. Longitudinal studies have demonstrated QEEG differences between mild cognitively impaired (MCI) elderly who go on to decline and those who do not. This study focuses on normal elderly with subjective cognitive complaints to assess the utility of QEEG in predicting future decline within 7 years. Forty-four normal elderly received extensive clinical, neurocognitive and QEEG examinations at baseline. All study subjects (N = 44) had only subjective complaints but no objective evidence of cognitive deficit (evaluated using the Global Deterioration Scale [GDS] score, GDS stage = 2) at baseline and were re-evaluated during 7-9 year follow-up. Baseline QEEGs of Decliners differed significantly (p < 0.0001, by MANOVA) from Non-Decliners, characterized by increases in theta power, slowing of mean frequency, and changes in covariance among regions, especially on the right hemisphere. Using logistic regression, an R2 of 0.93 (p < 0.001) was obtained between baseline QEEG features and probability of future decline, with an overall predictive accuracy of 90%. These data indicate high sensitivity and specificity for baseline QEEG as a differential predictor of future cognitive state in normal, subjectively impaired elderly.

Addition of a frequency-weighted score to the Behavioral Pathology in Alzheimer's Disease Rating Scale: the BEHAVE-AD-FW: methodology and reliability.

The Behavioral Pathology in Alzheimer's Disease Rating Scale (BEHAVE-AD) is a well-established instrument, designed to assess potentially remediable behavioral symptoms in Alzheimer's disease (AD) patients as well as to evaluate treatment outcome. It consists of 25 symptoms grouped into seven categories. Each symptom is scored on the basis of severity on a four-point scale. A knowledgeable caregiver is queried and items are scored on the basis of symptoms noted in the preceding two weeks. Reliability, construct validity and criterion validity data for the BEHAVE-AD have previously been published. Because of the significance of psychopathology in dementia, it is necessary to optimally describe and define the nature, magnitude and prevalence of behavioral symptomatology. Accordingly, a frequency component was added to each of the 25 items of the BEHAVE-AD scale. The objective of the present report is to describe this new Behavioral Pathology in Alzheimer's Disease Frequency-Weighted Severity Scale (BEHAVE-AD-FW) and to establish its inter-rater reliability. In this investigation the BEHAVE-AD-FW scale was administered to caregivers of 28 patients with either mildly impaired cognitive function or a dementia diagnosis. Two clinicians separately and independently rated the responses. Analyses determined that the intraclass correlation coefficients (ICCs) for the frequency component varied between 0.86 and 0.97 for each of the seven BEHAVE-AD categories (p(s) < 0.001). ICCs for the frequency-weighted scores (item severity score x item frequency score) ranged from 0.69 to 0.98 for the seven symptom categories (p(s) < 0.001). For the BEHAVE-AD-FW total scores, the ICC was 0.91 (P < 0.001). These results indicate that the frequency-weighted component is a reliable addition to the BEHAVE-AD scale.

Switching previous therapies for Alzheimer's disease to galantamine.

Acetylcholinesterase inhibitors (AChEIs) are the most frequently prescribed drugs for the treatment of Alzheimer's disease (AD). To date, donepezil is prescribed most often, but newer AChEIs have become available. Rivastigmine entered the pharmaceutics market for AD in 2000, and galantamine was approved for use in the United States in February 2001. Some patients with AD may already be taking a cholinesterase inhibitor, but they or their caregivers may want to change therapies for various reasons, such as lack of efficacy or poor tolerability. Therefore, defined protocols for discontinuing one therapy and initiating another therapy (ie, "switching") while maintaining efficacy and minimizing cholinergic toxicity will be essential. A post-hoc analysis of a clinical trial that enrolled patients with and without previous exposure to AChEIs indicated that the efficacy and tolerability of a second and different cholinesterase treatment were similar in both subpopulations of patients. These findings suggest that discontinuation of prior AChEI treatment is not predictive of future poor response to an effective treatment.

The cognitive syndrome of vascular dementia: implications for clinical trials.

Dementia is common among patients with cerebrovascular disease, particularly in a setting of one or more clinically evident strokes. Prior cohort and case studies have suggested that the cognitive syndrome of vascular dementia is characterized by predominant executive dysfunction, in contrast to the deficits in memory and language function that are typical of patients with Alzheimer disease. The course of cognitive decline may also differ between those dementia subtypes, with many, but not all, patients with vascular dementia exhibiting a stepwise course of decline caused by recurrent stroke and most patients with Alzheimer disease exhibiting a gradually progressive course of decline. The findings of prior studies of the cognitive syndrome of vascular dementia must be interpreted with caution, however, because of (1) possible inaccuracies in the determination of the dementia subtype and the loss of precision that might result from pooling heterogeneous subgroups of patients with vascular dementia, (2) difficulties inherent in identifying a pattern of strengths and weaknesses in patients who are required to have memory impairment and other deficits to meet operationalized criteria for dementia, and (3) the use of limited test batteries whose psychometric properties are incompletely understood. Specific questions that should be addressed by future studies are discussed.

Cognitive outcome measures.

Clinical trials of antidementia drugs must use a performance-based cognitive assessment as a primary outcome measure. There are well-established criteria for selecting or developing an optimal cognitive battery for Alzheimer disease (AD) trials that also apply to vascular dementia (VaD) trials. Because there is substantial overlap between the pattern of cognitive impairment in VaD and AD, the most efficient strategy for developing a VaD battery would be to begin with a well-established AD instrument and add subtests covering the additional domains that are more prominently impaired in VaD.

Suicide in two patients with a diagnosis of probable Alzheimer disease.

Two patients meeting the criteria for probable Alzheimer disease (AD) who were participating in a phase 3 clinical program with eptastigmine, a cholinesterase inhibitor, committed suicide. The first patient committed suicide by a self-inflicted gunshot wound to the head. The second patient committed suicide by jumping from a 19th story window. These two patients shared several clinical features with those found in the literature: being at the early stages of the disease, having a high level education, with preserved insight, having access to firearms, and being aware of not responding to pharmacological treatment.

Neuropsychological prediction of decline to dementia in nondemented elderly.

This study examined whether baseline neuropsychological performance in elderly assessed at a research clinic could accurately predict subsequent decline to dementia. Logistic regression analyses were applied to (1) 213 nondemented elderly with a Global Deterioration Scale (GDS) score of 1, 2, or 3, of whom 74 (35%) subsequently declined to any diagnosis of dementia, and (2) a diagnostically more restricted subset of this sample (N = 179), of whom 56 (31%) declined to a diagnosis of probable Alzheimer's disease (AD). The mean follow-up intervals were 3.8 and 3.7 years, respectively. A small set of baseline neuropsychological measures (especially a Paragraph Delayed Recall Test) significantly differentiated decliners from nondecliners to dementia or AD, after accounting for the contribution of age, sex, education, follow-up interval, and the rating of global clinical status. When examined in combination with the other factors or alone, the cognitive tests produced reasonably high specificities (91%-97%) and sensitivities (73%-89%). Using the obtained regression model, a similar level of classification accuracy was replicated on an independent sample of 119 nondemented elderly. A subanalysis of the high-risk GDS 3 subgroup indicated that cut scores from the paragraph test distinguished nondecliners from decliners (overall accuracies 87%-91%), implying that this assessment may accurately predict future cognitive status in elderly with mild cognitive impairment.

Diagnosis and treatment of Alzheimer disease and related disorders. Consensus statement of the American Association for Geriatric Psychiatry, the Alzheimer's Association, and the American Geriatrics Society.

OBJECTIVE: A consensus conference on the diagnosis and treatment of Alzheimer disease (AD) and related disorders was organized by the American Association for Geriatric Psychiatry, the Alzheimer's Association, and the American Geriatrics Society on January 4 and 5, 1997. The target audience was primary care physicians, and the following questions were addressed: (1) How prevalent is AD and what are its risk factors? What is its impact on society? (2) What are the different forms of dementia and how can they be recognized? (3) What constitutes safe and effective treatment for AD? What are the indications and contraindications for specific treatments? (4) What management strategies are available to the primary care practitioner? (5) What are the available medical specialty and community resources? (6) What are the important policy issues and how can policymakers improve access to care for dementia patients? (7) What are the most promising questions for future research? PARTICIPANTS: Consensus panel members and expert presenters were drawn from psychiatry, neurology, geriatrics, primary care, psychology, nursing, social work, occupational therapy, epidemiology, and public health and policy. EVIDENCE: The expert presenters summarized data from the world scientific literature on the questions posed to the panel. CONSENSUS PROCESS: The panelists listened to the experts' presentations, reviewed their background papers, and then provided responses to the questions based on these materials. The panel chairs prepared the initial drafts of the consensus statement, and these drafts were read by all panelists and edited until consensus was reached. CONCLUSIONS: Alzheimer disease is the most common disorder causing cognitive decline in old age and exacts a substantial cost on society. Although the diagnosis of AD is often missed or delayed, it is primarily one of inclusion, not exclusion, and usually can be made using standardized clinical criteria. Most cases can be diagnosed and managed in primary care settings, yet some patients with atypical presentations, severe impairment, or complex comorbidity benefit from specialist referral. Alzheimer disease is progressive and irreversible, but pharmacologic therapies for cognitive impairment and nonpharmacologic and pharmacologic treatments for the behavioral problems associated with dementia can enhance quality of life. Psychotherapeutic intervention with family members is often indicated, as nearly half of all caregivers become depressed. Health care delivery to these patients is fragmented and inadequate, and changes in disease management models are adding stresses to the system. New approaches are needed to ensure patients' access to essential resources, and future research should aim to improve diagnostic and therapeutic effectiveness.

Motor/psychomotor dysfunction in normal aging, mild cognitive decline, and early Alzheimer's disease: diagnostic and differential diagnostic features.

To determine the association between cognitive dysfunction and motor behavior in older adults, 41 cognitively normal elderly (NL), 25 nondemented patients exhibiting mild cognitive impairment (MI) and at risk for future decline to dementia, and 25 patients with mild (early) Alzheimer's disease (AD) were examined using a wide array of motor/psychomotor and cognitive assessments. The three groups were recruited from an aging and dementia research center and were composed of well-characterized physically healthy volunteers, with similar ages and gender distributions. The outcome measures included 16 motor/psychomotor tests categorized a priori into gross, fine, and complex, as well as eight cognitive tests of memory and language. Relative to the NL group, MI individuals performed poorly on cognitive, fine, and complex motor measures but not on gross motor tests; AD patients performed worse on cognitive and all motor domains. Differences in complex motor function persisted after adjustment for performance on cognitive and on less complex motor tests. Classification analyses showed similar accuracies in discriminating NL from MI and NL from AD cases for both complex motor (79% and 92% accuracy, respectively) and cognitive tests (80% and 93% accuracy, respectively). Less complex motor tests produced poorer accuracies. Among nondemented subjects, education correlated with several cognitive scores but no motor scores. These results indicate that motor impairment is an important aspect of cognitive decline in older adults. Motor/psychomotor assessments were found to be comparably sensitive to traditional tests of cognitive function in identifying persons affected by the earliest stages of AD pathology and may improve identification of at-risk nondemented elderly, especially among diversely educated individuals.

Measurement choices in multi-site studies of outcomes in dementia.

This paper summarizes the measurement choices made by selected current or recently completed multi-site projects with a common emphasis on measuring outcomes in dementia. Information on number of items and scoring, reason(s) for selecting the measure, and reliability and validity of the measure (either citations providing this information or a report of pertinent unpublished findings) is presented for eight domains: cognition, behavioral symptoms, physical health status, physical functioning and self-care abilities, quality of life, family/staff caregiver outcomes, service use, and cost. We found considerable reliance on the published literature as a guide to measurement choice, motivated largely by measures' superior psychometric properties, their ubiquity in the literature, and/or their brevity or ease of use. There is still evidence of "starting from scratch" in some domains, however. To the extent that these projects reflect the state of the art in dementia-relevant outcomes research, we conclude that comparison of outcomes across studies will continue to be problematic. However, as long as dissemination of methodological as well as substantive findings continues to characterize outcome studies in dementia, there is hope that a more congruent view of how to assess key outcomes in dementia will emerge.

Assessing cognition in Alzheimer disease research.

Because cognitive impairment is the central, defining symptom of Alzheimer disease, cognitive assessments commonly are used as primary or secondary measures of outcome in Alzheimer disease research. The authors review the cognitive functions that decline in this neurodegenerative disease and summarize the necessary features of appropriate cognitive performance tests. The characteristics, strengths, and weaknesses of the major cognitive batteries employed as outcome measures in Alzheimer disease research are reviewed. Finally, the recent contributions to the development of cognitive measures by the Alzheimer's Disease Cooperative Study are presented briefly, followed by discussion of some critical issues for future test development.

Patterns of motor impairement in normal aging, mild cognitive decline, and early Alzheimer's disease.

In order to determine the relationship between cognitive dysfunction and motor behavior in older adults, 41 cognitively normal elderly (NL), 25 cases exhibiting mild cognitive impairment (MI), and 25 patients with mild Alzheimer's disease (AD) were examined using a broad array to motor/psychomotor and cognitive tests. Relative to the NL group, MI individuals (at risk for future decline to AD) performed worse on tasks involving fine and complex motor function (e.g., tracking and manual dexterity). AD patients also exhibited motor dysfunction on tasks assessing relatively more rudimentary motor control. Motor tasks were able to distinguish NL vs MI and NL vs mild AD individuals as effectively as cognitive tests of memory and language. These results indicate that motor impairment is an important aspect of cognitive decline in older adults. Motor/psychomotor assessments may be comparably sensitive to traditional tests of cognitive function in identifying persons affected by the earliest stages of AD pathology.