Alzheimer Disease: Foster NL

Foster NL, Andersen TC, Zamrini EY. · Center for Alzheimer's Care, Imaging, and Research, Department of Neurology, University of Utah, Salt Lake City, UT, USA. · Alzheimers Dement. · Pubmed #19328451 No free full text.

Abstract: Advancing the development of drugs for the prevention and treatment of Alzheimer's disease (AD) is dependent on the ability of investigators to identify, recruit, and retain appropriate subjects in clinical trials. Innovations in care that link primary-care providers with AD researchers can help overcome barriers to early, specific diagnosis and access to research studies. Collaborative care provides a new paradigm for the mutual benefit of patients, providers, and AD research. Recommendations to achieve this goal include funding clinical centers of excellence in AD, linked with community physicians to utilize clinical care and initial evaluations as early entry points for patients into AD research, and funding mini-fellowships for community physicians. Reimbursement for dementia care should be expanded to include periodic cognitive assessments for at-risk individuals, medically directed dementia education, and diagnostic imaging and biomarkers. These innovations can simultaneously improve the translation of research advances, and benefit AD research.

Weintraub S, Salmon D, Mercaldo N, Ferris S, Graff-Radford NR, Chui H, Cummings J, DeCarli C, Foster NL, Galasko D, Peskind E, Dietrich W, Beekly DL, Kukull WA, Morris JC. · Cognitive Neurology and Alzheimer's Disease Center, Northwestern University Feinberg School of Medicine, 320 E. Superior, Searle 11-467, Chicago, IL 60611, USA. · Alzheimer Dis Assoc Disord. · Pubmed #19474567 No free full text.

Abstract: The neuropsychologic test battery from the Uniform Data Set (UDS) of the Alzheimer's Disease Centers (ADC) program of the National Institute on Aging consists of brief measures of attention, processing speed, executive function, episodic memory, and language. This paper describes development of the battery and preliminary data from the initial UDS evaluation of 3268 clinically cognitively normal men and women collected over the first 24 months of utilization. The subjects represent a sample of community-dwelling, individuals who volunteer for studies of cognitive aging. Subjects were considered "clinically cognitively normal" based on clinical assessment, including the Clinical Dementia Rating scale and the Functional Assessment Questionnaire. The results demonstrate performance on tests sensitive to cognitive aging and to the early stages of Alzheimer disease in a relatively well-educated sample. Regression models investigating the impact of age, education, and sex on test scores indicate that these variables will need to be incorporated in subsequent normative studies. Future plans include: (1) determining the psychometric properties of the battery; (2) establishing normative data, including norms for different ethnic minority groups; and (3) conducting longitudinal studies on cognitively normal subjects, individuals with mild cognitive impairment, and individuals with Alzheimer disease and other forms of dementia.

Foster NL, Wang AY, Tasdizen T, Fletcher PT, Hoffman JM, Koeppe RA. · Center for Alzheimer's Care, Imaging and Research, Department of Neurology, University of Utah, Salt Lake City, UT, USA. · Alzheimers Dement. · Pubmed #18631997 No free full text.

Abstract: Positron emission tomography (PET) with 18F-fluorodeoxyglucose (FDG-PET) thus far rarely has been used to advance the development of new treatments for Alzheimer's disease (AD). Now that FDG-PET with standard acquisition protocols for dementia is widely available, change in cerebral glucose metabolism is a feasible outcome variable for clinical drug trials. Individual analysis of FDG-PET results also might prove valuable. FDG-PET can detect metabolic changes very early in the course of AD and identify subjects for earlier treatment. FDG-PET reliably distinguishes AD from frontotemporal dementia so that only those most likely to benefit are enrolled in trials. Finally, objectively identifying phenotypic variations of AD with FDG-PET might have pathogenic and prognostic implications that can be used for personalized treatment approaches. The judicious use of FDG-PET is needed to accelerate the evaluation of promising new drugs and more rationally target treatments for dementing diseases.

Langa KM, Foster NL, Larson EB. · Division of General Medicine, Department of Medicine, University of Michigan Medical School, Ann Arbor, USA. · JAMA. · Pubmed #15598922 links to  free full text

Abstract: CONTEXT: The prevalence of mixed dementia, defined as the coexistence of Alzheimer disease (AD) and vascular dementia (VaD), is likely to increase as the population ages. OBJECTIVES: To provide an overview of the diagnosis, pathophysiology, and interaction of AD and VaD in mixed dementia, and to provide a systematic literature review of the current evidence for the pharmacologic therapy of mixed dementia. DATA SOURCES, STUDY SELECTION, AND DATA EXTRACTION: The Cochrane Database of Systematic Reviews was searched using the keyword dementia. MEDLINE was searched for English-language articles published within the last 10 years using the keywords mixed dementia, the combination of keywords Alzheimer disease, cerebrovascular disorders, and drug therapy, and the combination of keywords vascular dementia and drug therapy. EVIDENCE SYNTHESIS: Dementia is more likely to be present when vascular and AD lesions coexist, a situation that is especially common with increasing age. The measured benefits in clinical trials for the treatment of mixed dementia are best described as statistically significant differences in cognitive test scores and clinician and caregiver impressions of change. In these studies, the control groups' scores typically decline while the treatment groups improve slightly or decline to a lesser degree over the study period. Nevertheless, even the patients who experience treatment benefits eventually decline. Cholinesterase inhibitor (ChI) therapy for mixed dementia shows modest clinical benefits that are similar to those found for ChI treatment of AD. The N-methyl-D-aspartate (NMDA) antagonist memantine also shows modest clinical benefits for the treatment of moderate to severe AD and mild to moderate VaD, but it has not been studied specifically in mixed dementia. The treatment of cardiovascular risk factors, especially hypertension, may be a more effective way to protect brain function as primary, secondary, and tertiary prevention for mixed dementia. CONCLUSIONS: Currently available medications provide only modest clinical benefits once a patient has developed mixed dementia. Cardiovascular risk factor control, especially for hypertension and hyperlipidemia, as well as other interventions to prevent recurrent stroke, likely represent important strategies for preventing or slowing the progression of mixed dementia. Additional research is needed to define better what individuals and families hope to achieve from dementia treatment and to determine the most appropriate use of medication to achieve these goals.

Foster NL. · Taubman Center, Ann Arbor, MI 48109-0316, USA. · J Geriatr Psychiatry Neurol. · Pubmed #11794447 No free full text.

Abstract: Evaluating and treating dementia is intellectually demanding and enormously satisfying. However, physicians providing dementia care also confront unique challenges that cause discomfort and overwhelming frustration unless they are recognized and overcome. Physicians must care for individuals who do not adopt the "sick role." They must establish and maintain rapport with patients while also approaching collateral sources to obtain a complete history. They must develop a complex alliance with the patient, caregivers, community agencies, and other health professionals to provide effective treatment. Physicians must relate "bad news" to several people at once who are unequally prepared for it, while dealing with their own diagnostic uncertainty. Furthermore, physicians must honor patient autonomy and balance it with the needs of caregivers. Since the demands of providing dementia care are not typical of most medical practice, the special attributes needed are often not taught to students or adequately reimbursed by health insurance. The quality of dementia care will improve when strategies that address these aspects of care for patients with dementia are widely adopted.

Grundman M, Petersen RC, Ferris SH, Thomas RG, Aisen PS, Bennett DA, Foster NL, Jack CR, Galasko DR, Doody R, Kaye J, Sano M, Mohs R, Gauthier S, Kim HT, Jin S, Schultz AN, Schafer K, Mulnard R, van Dyck CH, Mintzer J, Zamrini EY, Cahn-Weiner D, Thal LJ, Anonymous00151. · Alzheimer's Disease Cooperative Study, Department of Neurosciences, University of California-San Diego, 8950 Villa La Jolla Drive, Suite 227, La Jolla, CA 92037, USA. · Arch Neurol. · Pubmed #14732621 links to  free full text

Abstract: BACKGROUND: Mild cognitive impairment (MCI) represents a transitional state between the cognitive changes of normal aging and very early dementia and is becoming increasingly recognized as a risk factor for Alzheimer disease (AD). The Memory Impairment Study (MIS) is a multicenter clinical trial in patients with MCI designed to evaluate whether vitamin E or donepezil is effective at delaying the time to a clinical diagnosis of AD. OBJECTIVE: To describe the baseline characteristics of patients with MCI recruited for the MIS and compare them with those of elderly controls and patients with AD in another clinical trial. DESIGN: Descriptive and comparative study of patients with MCI participating in a multicenter clinical trial. SETTING: Memory disorder centers in the United States and Canada. PATIENTS: A total of 769 patients with MCI, 107 cognitively normal elderly controls, 122 patients with very mild AD (Clinical Dementia Rating [CDR] 0.5), and 183 patients with mild AD (CDR 1.0) were evaluated. Patients in the MIS met operational criteria for amnestic MCI. Controls were recruited in parallel with the MCI group, underwent the same assessments, and had a CDR of 0. MAIN OUTCOME MEASURES: Clinical, neuropsychologic, functional, neuroimaging, and genetic measures. RESULTS: Mean +/- SD Alzheimer's Disease Assessment Scale-Cognitive Subscale scores were 5.6 +/- 3.3 for controls, 11.3 +/- 4.4 for patients with MCI, 18.0 +/- 6.2 for the AD CDR 0.5 group, and 25.2 +/- 8.8 for the AD CDR 1.0 group. Compared with controls, patients with MCI were most impaired on memory tasks, with less severe impairments in other cognitive domains. Patients with MCI were more likely than controls but less likely than patients with AD to carry the apolipoprotein E epsilon4 allele. Patients with MCI had hippocampal volumes that were intermediate between those of controls and patients with AD. CONCLUSIONS: Patients with MCI had a predominant memory impairment with relative sparing of other cognitive domains and were intermediate between clinically normal individuals and patients with AD on cognitive and functional ratings. These results demonstrate the successful implementation of operational criteria for this unique group of at-risk patients in a multicenter clinical trial.

Higdon R, Foster NL, Koeppe RA, DeCarli CS, Jagust WJ, Clark CM, Barbas NR, Arnold SE, Turner RS, Heidebrink JL, Minoshima S. · University of Washington, Seattle, USA. · Stat Med. · Pubmed #14716732 No free full text.

Abstract: Flurodeoxyglucose positron emission tomography (FDG-PET) is being explored to determine its ability to differentiate between a diagnosis of Alzheimer's disease (AD) and fronto-temporal dementia (FTD). We have examined statistical discrimination procedures to help achieve this purpose and compared the results to visual ratings of FDG-PET images. The methods are applied to a data set of 48 subjects with autopsy confirmed diagnoses of AD or FTD (these subjects come from a multi-centre collaborative study funded by the National Alzheimer's Coordinating Center). FDG-PET images are composed of thousands of voxels (volume elements) so one is left with a situation where there are vastly more variables than subjects. Therefore, it is necessary to perform a data reduction before a statistical procedure can be applied. Approaches using both the entire image and summary statistics calculated on a number of volumes of interest (VOI) are examined. We performed the data reduction techniques of principal components analysis (PCA) and partial least-squares (PLS) on the entire image and then used linear discriminant analysis (LDA), quadratic (QDA) or logistic regression (LR) to classify subjects as having AD or FTD. Some of these methods achieve diagnostic accuracy (as assessed by leave-one-out cross-validation) that is similar to visual ratings by expert raters. Methods using PLS appear to be more successful. Averaging or using VOI data may also be helpful.

Doody RS, Dunn JK, Clark CM, Farlow M, Foster NL, Liao T, Gonzales N, Lai E, Massman P. · Baylor College of Medicine Alzheimer's Disease Research Center (AGO-8664), Houston, Tex 77030-3498, USA. · Dement Geriatr Cogn Disord. · Pubmed #11351141 No free full text.

Abstract: OBJECTIVE: To compare rates of cognitive decline between probable Alzheimer's disease (AD) patients treated with long-duration cholinesterase inhibitors (ChE-Is) and those who remained untreated. BACKGROUND: ChE-Is, including donepezil and tracrine, have shown beneficial effects on cognition and global functioning in patients with AD. The duration of these benefits is unknown because the longest double-blind placebo-controlled studies reported were only approximately 6 months long. Ethical concerns regarding randomization of patients to placebo for long periods make it difficult to undertake trials of longer duration. METHODS: We identified patients in 4 AD centers who were or were not consistently treated with ChE-Is and who had demographic, psychometric and follow-up data. We compared 205 ChE-I-treated and 218 untreated AD patients on baseline variables hypothesized to differ between these groups, on baseline Mini Mental Status Examination (MMSE) scores and on rates of MMSE change at 1 year. The analysis was performed initially with all ChE-I-treated patients as a single group versus untreated subjects, and then with donepezil versus untreated subjects and tacrine versus untreated subjects. RESULTS: As expected, treated and untreated patients differed with respect to age, education, ethnicity, percentage of community dwelling and exact days of follow-up (ANOVA and chi2) in several comparisons, but did not differ on baseline MMSE score. These baseline variables were highly intercorrelated. MMSE scores declined significantly more slowly after 1 year of ChE-I treatment compared to untreated patients (p = 0.05) after controlling for baseline differences in age, education, ethnicity and percentage of community dwelling. Slowing of decline was significant in the donepezil-treated patients (p = 0.007) but not in the tacrine-treated group (p = 0.33). CONCLUSIONS: This study, utilizing concurrent, nonrandomized controls, suggests that donepezil continues to have efficacy over at least the first year of therapy. Other studies are needed to determine whether the benefits are maintained beyond 1 year.

Teri L, Logsdon RG, Peskind E, Raskind M, Weiner MF, Tractenberg RE, Foster NL, Schneider LS, Sano M, Whitehouse P, Tariot P, Mellow AM, Auchus AP, Grundman M, Thomas RG, Schafer K, Thal LJ, Anonymous00040. · University of Washington, Department of Psychosocial and Community Health, Seattle 98195-7263, USA. · Neurology. · Pubmed #11087767 No free full text.

Abstract: BACKGROUND: Treatment of agitation is a crucial problem in the care of patients with AD. Although antipsychotic and antidepressant medications and behavior management techniques (BMT) have each been used to treat agitation, clinical trials of these treatments have been characterized by small sample sizes and uncontrolled treatment designs. OBJECTIVE: To compare haloperidol, trazodone, and BMT with placebo in the treatment of agitation in AD outpatients. METHODS: A total of 149 patients with AD and their caregivers participated in a randomized, placebo-controlled, multicenter trial. Blind assessment was conducted at baseline and after 16 weeks of treatment. The three active treatments were haloperidol, trazodone, and BMT. The Alzheimer's Disease Cooperative Study Clinical Global Impression of Change was the primary outcome measure. Secondary outcomes included patient agitation, cognition, and function, and caregiver burden. RESULTS: Thirty-four percent of subjects improved relative to baseline. No significant differences on outcome were obtained between haloperidol (mean dose, 1.8 mg/d), trazodone (mean dose, 200 mg/d), BMT, or placebo. Significantly fewer adverse events of bradykinesia and parkinsonian gait were evident in the BMT arm. No other significant difference in adverse events was seen. Symptoms did not respond differentially to the different treatments. CONCLUSIONS: Comparable modest reductions in agitation occurred in patients receiving haloperidol, trazodone, BMT, and placebo. More effective pharmacologic, nonpharmacologic, and combination treatments are needed.

Langbaum JB, Chen K, Lee W, Reschke C, Bandy D, Fleisher AS, Alexander GE, Foster NL, Weiner MW, Koeppe RA, Jagust WJ, Reiman EM, Anonymous00091. · Banner Alzheimer's Institute and Banner Good Samaritan PET Center, Phoenix, AZ, USA. · Neuroimage. · Pubmed #19349228 No free full text.

Abstract: In mostly small single-center studies, Alzheimer's disease (AD) is associated with characteristic and progressive reductions in fluorodeoxyglucose positron emission tomography (PET) measurements of the regional cerebral metabolic rate for glucose (CMRgl). The AD Neuroimaging Initiative (ADNI) is acquiring FDG PET, volumetric magnetic resonance imaging, and other biomarker measurements in a large longitudinal multi-center study of initially mildly affected probable AD (pAD) patients, amnestic mild cognitive impairment (aMCI) patients, who are at increased AD risk, and cognitively normal controls (NC), and we are responsible for analyzing the PET images using statistical parametric mapping (SPM). Here we compare baseline CMRgl measurements from 74 pAD patients and 142 aMCI patients to those from 82 NC, we correlate CMRgl with categorical and continuous measures of clinical disease severity, and we compare apolipoprotein E (APOE) varepsilon4 carriers to non-carriers in each of these subject groups. In comparison with NC, the pAD and aMCI groups each had significantly lower CMRgl bilaterally in posterior cingulate, precuneus, parietotemporal and frontal cortex. Similar reductions were observed when categories of disease severity or lower Mini-Mental State Exam (MMSE) scores were correlated with lower CMRgl. However, when analyses were restricted to the pAD patients, lower MMSE scores were significantly correlated with lower left frontal and temporal CMRgl. These findings from a large, multi-site study support previous single-site findings, supports the characteristic pattern of baseline CMRgl reductions in AD and aMCI patients, as well as preferential anterior CMRgl reductions after the onset of AD dementia.

Khachaturian ZS, Snyder PJ, Doody R, Aisen P, Comer M, Dwyer J, Frank RA, Holzapfel A, Khachaturian AS, Korczyn AD, Roses A, Simpkins JW, Schneider LS, Albert MS, Egge R, Deves A, Ferris S, Greenberg BD, Johnson C, Kukull WA, Poirier J, Schenk D, Thies W, Gauthier S, Gilman S, Bernick C, Cummings JL, Fillit H, Grundman M, Kaye J, Mucke L, Reisberg B, Sano M, Pickeral O, Petersen RC, Mohs RC, Carrillo M, Corey-Bloom JP, Foster NL, Jacobsen S, Lee V, Potter WZ, Sabbagh MN, Salmon D, Trojanowski JQ, Wexler N, Bain LJ. · Lou Ruvo Brain Institute, Las Vegas, NV 89106, USA. · Alzheimers Dement. · Pubmed #19328434 No free full text.

Abstract: This document proposes an array of recommendations for a National Plan of Action to accelerate the discovery and development of therapies to delay or prevent the onset of disabling symptoms of Alzheimer's disease. A number of key scientific and public-policy needs identified in this document will be incorporated by the Alzheimer Study Group into a broader National Alzheimer's Strategic Plan, which will be presented to the 111th Congress and the Obama administration in March 2009. The Alzheimer's Strategic Plan is expected to include additional recommendations for governance, family support, healthcare, and delivery of social services.

Habeck C, Foster NL, Perneczky R, Kurz A, Alexopoulos P, Koeppe RA, Drzezga A, Stern Y. · Taub Institute, Columbia University Medical Center, New York, NY 10032, USA. · Neuroimage. · Pubmed #18343688 links to  free full text

Abstract: We performed univariate and multivariate discriminant analysis of FDG-PET scans to evaluate their ability to identify Alzheimer's disease (AD). FDG-PET scans came from two sources: 17 AD patients and 33 healthy elderly controls were scanned at the University of Michigan; 102 early AD patients and 20 healthy elderly controls were scanned at the Technical University of Munich, Germany. We selected a derivation sample of 20 AD patients and 20 healthy controls matched on age with the remainder divided into 5 replication samples. The sensitivity and specificity of diagnostic AD-markers and threshold criteria from the derivation sample were determined in the replication samples. Although both univariate and multivariate analyses produced markers with high classification accuracy in the derivation sample, the multivariate marker's diagnostic performance in the replication samples was superior. Further, supplementary analysis showed its performance to be unaffected by the loss of key regions. Multivariate measures of AD utilize the covariance structure of imaging data and provide complementary, clinically relevant information that may be superior to univariate measures.

Foster NL, Heidebrink JL, Clark CM, Jagust WJ, Arnold SE, Barbas NR, DeCarli CS, Turner RS, Koeppe RA, Higdon R, Minoshima S. · Center for Alzheimer's Care, Imaging and Research and Department of Neurology, University of Utah, USA. · Brain. · Pubmed #17704526 links to  free full text

Abstract: Distinguishing Alzheimer's disease (AD) and frontotemporal dementia (FTD) currently relies on a clinical history and examination, but positron emission tomography with [(18)F] fluorodeoxyglucose (FDG-PET) shows different patterns of hypometabolism in these disorders that might aid differential diagnosis. Six dementia experts with variable FDG-PET experience made independent, forced choice, diagnostic decisions in 45 patients with pathologically confirmed AD (n = 31) or FTD (n = 14) using five separate methods: (1) review of clinical summaries, (2) a diagnostic checklist alone, (3) summary and checklist, (4) transaxial FDG-PET scans and (5) FDG-PET stereotactic surface projection (SSP) metabolic and statistical maps. In addition, we evaluated the effect of the sequential review of a clinical summary followed by SSP. Visual interpretation of SSP images was superior to clinical assessment and had the best inter-rater reliability (mean kappa = 0.78) and diagnostic accuracy (89.6%). It also had the highest specificity (97.6%) and sensitivity (86%), and positive likelihood ratio for FTD (36.5). The addition of FDG-PET to clinical summaries increased diagnostic accuracy and confidence for both AD and FTD. It was particularly helpful when raters were uncertain in their clinical diagnosis. Visual interpretation of FDG-PET after brief training is more reliable and accurate in distinguishing FTD from AD than clinical methods alone. FDG-PET adds important information that appropriately increases diagnostic confidence, even among experienced dementia specialists.

Fletcher PT, Powell S, Foster NL, Joshi SC. · School of Computing, University of Utah, Salt Lake City, UT, USA. · Inf Process Med Imaging. · Pubmed #17633720 No free full text.

Abstract: In this paper we describe a new method for quantifying metabolic asymmetry modulo structural hemispheric differences. The study of metabolic asymmetry in Alzheimer's disease (AD) serves as a driving application. The approach is based on anatomical atlas construction by large deformation diffeomorphic metric mapping (LDDMM) first introduced in [1]. Using invariance properties of the LDDMM, we define a structurally symmetric coordinate frame in which metabolic asymmetries between the left and the right hemispheres can be studied. This structurally symmetric coordinate system of each subject provides the correspondence between left and right hemispheric structures in an individual brain. These correspondences are used for measuring metabolic asymmetry modulo structural asymmetry. Again using the atlas construction framework, we build a common symmetric coordinate system of a entire population. The metabolic asymmetry maps of individuals in a population under study are mapped into the common structurally symmetric coordinate frame, allowing for a statistical description of the populations metabolic asymmetry. In this paper we prove certain invariance properties of the LDDMM atlas construction framework that make the definition of structurally symmetric coordinate systems possible. We present results from applying the methodology to images from the Alzheimer's Disease Neuroimaging Initiative (ADNI).

Morris JC, Weintraub S, Chui HC, Cummings J, Decarli C, Ferris S, Foster NL, Galasko D, Graff-Radford N, Peskind ER, Beekly D, Ramos EM, Kukull WA. · Washington University, St. Louis, MO 63108, USA. · Alzheimer Dis Assoc Disord. · Pubmed #17132964 No free full text.

Abstract: A Clinical Task Force, composed of clinical leaders from Alzheimer's Disease Centers (ADC), was convened by the National Institute on Aging to develop a uniform set of assessment procedures to characterize individuals with mild Alzheimer disease and mild cognitive impairment in comparison with nondemented aging. The resulting Uniform Data Set (UDS) defines a common set of clinical observations to be collected longitudinally on ADC participants in accordance with standard methods. The UDS was implemented at all ADCs on September 1, 2005. Data obtained with the UDS are submitted to the National Alzheimer's Coordinating Center and represent a unique and valuable source of data to support and stimulate collaborative research.

Langa KM, Larson EB, Wallace RB, Fendrick AM, Foster NL, Kabeto MU, Weir DR, Willis RJ, Herzog AR. · Division of General Medicine, Department of Medicine, University of Michigan Medical School, Ann Arbor, 48109-0429, USA. · Alzheimer Dis Assoc Disord. · Pubmed #15249853 No free full text.

Abstract: The number of older individuals with dementia will likely increase significantly in the next decades, but there is currently limited information regarding the out-of-pocket expenditures (OOPE) for medical care made by cognitively impaired individuals and their families. We used data from the 1993 and 1995 Asset and Health Dynamics Study, a nationally representative longitudinal survey of older Americans, to determine the OOPE for individuals with and without dementia. Dementia was identified in 1993 using a modified version of the Telephone Interview for Cognitive Status for self-respondents, and proxy assessment of memory and judgment for proxy respondents. In 1995, respondents reported OOPE over the prior 2 years for: 1) hospital and nursing home stays, 2) outpatient services, 3) home care, and 4) prescription medications. The adjusted mean annual OOPE was 1,350 US dollars for those without dementia, 2,150 US dollars for those with mild/moderate dementia, and 3,010 US dollars for those with severe dementia (p < 0.01). Expenditures for hospital/nursing home care (1,770 per year US dollars) and prescription medications (800 per year US dollars) were the largest OOPE components for those with severe dementia. We conclude that dementia is independently associated with significantly higher OOPE for medical care compared with those with normal cognitive function. Severe dementia is associated with a doubling of OOPE, mainly due to higher payments for long-term care. Given that the number of older Americans with dementia will likely increase significantly in the coming decades, changes in public funding aimed at reducing OOPE for both long-term care and prescription medications would have considerable impact on individuals with dementia and their families.

Banaszak-Holl J, Fendrick AM, Foster NL, Herzog AR, Kabeto MU, Kent DM, Straus WL, Langa KM. · Department of Health Management and Policy, School of Public Health, University of Michigan, Ann Arbor, 48109-2029, USA. · Alzheimer Dis Assoc Disord. · Pubmed #15249852 No free full text.

Abstract: This study determines whether prevalence and predictors of nursing home admission changed in the 1990s, during a period of dramatic changes in the service provision for and medical care of chronic impairments. Data from the 1993-2000 surveys of the Asset and Health Dynamics Among the Oldest Old (AHEAD) Study, a longitudinal and nationally representative sample, were used. Proportional hazard models were used to determine the effects of dementia, physical functioning, clinical conditions, and sociodemographics on the likelihood of nursing home admission. Of the 6,676 respondents, 17% were admitted to a nursing home. Models excluding functional impairment demonstrated significant effects of chronic medical conditions and dementia on the risk of institutionalization. After controlling for functional impairment, dementia still had significant and strong effects on institutionalization but clinical conditions did not, suggesting that the impact of dementia goes beyond its effect on physical functioning. Nursing home admissions did not decrease during the study period, and the impact of dementia on the risk of nursing home admission did not decrease. Interventions for individuals with dementia should impact the behavioral aspects of the condition and slow disease progression in addition to improving physical functioning.

Moretti P, Lieberman AP, Wilde EA, Giordani BI, Kluin KJ, Koeppe RA, Minoshima S, Kuhl DE, Seltzer WK, Foster NL. · Departments of Neurology, University of Michigan, Ann Arbor 48109, USA. · Neurology. · Pubmed #15159497 No free full text.

Abstract: A four-generation pedigree exhibiting early-onset autosomal dominant Alzheimer disease (AD) with spastic paraplegia, dystonia, and dysarthria due to a novel 6-nucleotide insertional mutation in exon 3 of the presenilin 1 gene (PS1) is described. Serial examinations, PET scans, and autopsy revealed that the mutation in this highly conserved portion of PS1 causes an aggressive dementia that maintains the usual regional hierarchy of disease pathology while extending abnormalities into more widespread brain areas than typically seen in AD.

Minoshima S, Foster NL, Sima AA, Frey KA, Albin RL, Kuhl DE. · Department of Internal Medicine, University of Michigan Medical School, Geriatrics Research, Education, and Clinical Center, Ann Arbor, USA. · Ann Neurol. · Pubmed #11558792 No free full text.

Abstract: Seeking antemortem markers to distinguish Dementia with Lewy bodies (DLB) and Alzheimer's disease (AD), we examined brain glucose metabolism of DLB and AD. Eleven DLB patients (7 Lewy body variant of AD [LBVAD] and 4 pure diffuse Lewy body disease [DLBD]) who had antemortem position emission tomography imaging and autopsy confirmation were compared to 10 autopsy-confirmed pure AD patients. In addition, 53 patients with clinically-diagnosed probable AD, 13 of whom later fulfilled clinical diagnoses of DLB, were examined. Autopsy-confirmed AD and DLB patients showed significant metabolic reductions involving parietotemporal association, posterior cingulate, and frontal association cortices. Only DLB patients showed significant metabolic reductions in the occipital cortex, particularly in the primary visual cortex (LBVAD -23% and DLBD -29% vs AD -8%), which distinguished DLB versus AD with 90% sensitivity and 80% specificity. Multivariate analysis revealed that occipital metabolic changes in DLB were independent from those in the adjacent parietotemporal cortices. Analysis of clinically diagnosed probable AD patients showed a significantly higher frequency of primary visual metabolic reduction among patients who fulfilled later dinical criteria for DLB. In these patients, occipital hypometabolism preceded some clinical features of DLB. Occipital hypometabolism is a potential antemortem marker to distinguish DLB versus AD.

Connell CM, Shaw BA, Holmes SB, Foster NL. · Michigan Alzheimer's Disease Research Center, University of Michigan School of Public Health, Ann Arbor, MI 48109-2029, USA. · Alzheimer Dis Assoc Disord. · Pubmed #11522931 No free full text.

Abstract: Current levels of participation in Alzheimer disease (AD) research are inadequate, particularly among nonwhites. This study was conducted to examine caregivers' attitudes toward their family members' participation in AD research. Six focus group interviews were conducted with 38 white and 12 African-American caregivers of participants enrolled in clinical research projects. Both white and African-American families participated in research to help their care recipients and future generations, receive support from the clinical and research staff, and obtain feedback about patient status and research results. Among white caregivers, primary barriers to participation in research included the potential for no direct benefit, problems with the procedures and tests involved, lack of time and resources, and difficulty accepting the diagnosis. Among African-American caregivers, primary barriers included general skepticism about the research process and firmly established attitudes about medical treatment and help seeking that serve as disincentives to research participation. To maximize the perceived benefits of research participation, potential participants should have access to regular personal contact with staff, information about health status changes in the care recipient, and the short-term and long-term results of the research studies in which they are participants. In addition, researchers should be sensitive to the concerns that may serve as barriers to participation, particularly among African Americans.

Bozoki A, Giordani B, Heidebrink JL, Berent S, Foster NL. · Department of Neurology, University of Michigan, TC1913A, 1500 E Medical Center Dr, Ann Arbor, MI 48109-0322, USA. · Arch Neurol. · Pubmed #11255444 links to  free full text

Abstract: BACKGROUND: Some elderly individuals exhibit significant memory deficits but do not have dementia because their general intellect is preserved and they have no impairments in everyday activities. These symptoms are often a precursor to Alzheimer disease (AD), but sometimes dementia does not occur, even after many years of observation. There is currently no reliable way to distinguish between these 2 possible outcomes in an individual patient. We hypothesized that clear impairments in at least 1 cognitive domain in addition to memory would help identify those who will progress to AD. OBJECTIVE: To determine whether nondemented patients with impairments in memory and other domains are more likely than those with memory impairment alone to develop AD. DESIGN AND METHODS: In a retrospective study, we evaluated 48 nondemented, nondepressed patients with clinical and psychometric evidence of memory impairment who were followed up for 2 or more years. Age-adjusted normative criteria were used to identify whether additional impairments were present in language, attention, motor visuospatial function, and verbal fluency at this initial evaluation. The presence or absence of dementia after 2 years and at the most recent neurological evaluation was compared in subjects with normal scores in all 4 of these cognitive areas apart from memory (M-) and those with impairment in 1 or more of these areas (M+). Outcomes were adjusted for age, intelligence at initial evaluation, and years of education. RESULTS: Of the 48 nondemented patients with memory loss, 17 met M- criteria, leaving 31 in the M+ group. Deficits in block design were the most frequent abnormality other than memory loss. At the 2-year follow-up, 1 M- subject (6%) had progressed to AD, whereas 15 (48%) of the M+ group had progressed to AD (P =.003). At the most recent follow-up (mean +/- SD, 4.0 +/- 2.0 years), 4 (24%) of the M- patients progressed to AD compared with 24 (77%) of the M+ patients (P<.001). CONCLUSIONS: Among nondemented elderly patients, memory loss alone rarely progresses to dementia in the subsequent 2 years. However, the risk of dementia is significantly increased among patients with clear cognitive impairments beyond memory loss. Further study is needed to determine whether patients with impairments limited to memory loss have a distinctive clinical course or pathophysiology.

Zubieta JK, Koeppe RA, Frey KA, Kilbourn MR, Mangner TJ, Foster NL, Kuhl DE. · Department of Psychiatry, The University of Michigan, Neuroscience Building, 1103 East Huron Street, Ann Arbor, MI 48104-1687, USA. · Synapse. · Pubmed #11169777 No free full text.

Abstract: Cerebral cholinergic deficits have been described in Alzheimer disease (AD) and as a result of normal aging. At the present time, there are very limited options for the quantification of cholinergic receptors with in vivo imaging techniques such as PET. In the present study, we examined the feasibility of utilizing [11C]N-methyl-4-piperidyl benzilate (NMPB), a nonselective muscarinic receptor ligand, in the study of aging and neurodegenerative processes associated with cholinergic dysfunction. Based on prior data describing the accuracy of various kinetic methods, we examined the concentration of muscarinic receptors with [11C]NMPB and PET using two- and three-compartment kinetic models. Eighteen healthy subjects and six patients diagnosed with probable AD were studied. Pixel-by-pixel two-compartment model fits showed acceptable precision in the study of normal aging, with comparable results to those obtained with a more complex and less precise three-compartment model. Normal aging was associated with a reduction in muscarinic receptor binding in neocortical regions and thalamus. In AD patients, the three-compartment model appeared capable of dissociating changes in tracer transport from changes in receptor binding, but suffered from statistical uncertainty, requiring normalization to a reference region, and therefore limiting its potential use in the study of neurodegenerative processes. After normalization, no regional changes in muscarinic receptor concentrations were observed in AD.

Kuhl DE, Minoshima S, Frey KA, Foster NL, Kilbourn MR, Koeppe RA. · Department of Internal Medicine, University of Michigan, Ann Arbor, USA. · Ann Neurol. · Pubmed #10976649 No free full text.

Abstract: Based on surrogate assays of peripheral red blood cells, reports state that widely prescribed doses of donepezil hydrochloride provide nearly complete inhibition of cerebral cortical acetylcholinesterase activity in the treatment of Alzheimer's disease (AD). To test this, direct positron emission tomography measures of cerebral acetylcholinesterase activity were made in AD patients before and after treatment with donepezil (5 and 10 mg/day) for at least 5 weeks and compared with similar measures in normal controls who were untreated or after acute administration of another AChE inhibitor, physostigmine salicylate (1.5 mg/hr). After physostigmine, acetylcholinesterase inhibition averaged 52% in normal cerebral cortex. After donepezil, cerebral cortical inhibition in AD brain averaged only 27%. Clinical trials of this donepezil dose schedule are not testing the effect of nearly complete cerebral cortical inhibition.

Foster NL, Gombosi E, Teboe C, Little RJ. · Michigan Alzheimer's Disease Research Center and the Department of Neurology, University of Michigan, Ann Arbor, MI 48109, USA. · Stat Med. · Pubmed #10844716 No free full text.

Abstract: Clinical research databases can meet both research and clinical needs, but this ideal is seldom achieved. Priorities often differ for those who collect and ultimately use the data and those who develop data systems. Traditional database designs also create logistical barriers that hamper communication. The Michigan Alzheimer's Disease Research Center has developed a secure, distributed data system with centralized data entry that provides an intuitive, individually customized interface for investigators in their clinics, laboratories and offices. Data are kept in a form that can be readily understood without reference to a code-book. Investigators can modify and query their own copies of the database without knowledge of programming languages. Balancing centralized and distributed designs for research databases enhance the accuracy and completeness of data collection and increases the use of data for research and clinical care.

Minoshima S, Cross DJ, Foster NL, Henry TR, Kuhl DE. · Department of Internal Medicine, University of Michigan, Ann Arbor 48109, USA. · Ann N Y Acad Sci. · Pubmed #10672264 No free full text.

Abstract: These results suggest that neither the loss of entorhinal efferents nor cholinergic deficit explains all the metabolic features seen in very early AD. Given recent immunohistological evidence of massive glutamatergic synaptic alteration in early AD cortex and insights into neuronal and glial mechanisms of glucose metabolism, very early metabolic changes in AD probably reflect a significant impairment of glycolytic activities in the cortico-cortical glutamatergic systems in a preclinical stage of the disease. However, the exact mechanisms of such impairment in these neurons are yet to be determined.