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The objectives of this study were to review the diagnostic, International Classification of Disease, 9th Revision, Clinical Modification (ICD-9-CM), diagnosis related groups (DRGs), and common procedural terminology (CPT) coding and reimbursement issues (including Medicare Part B reimbursement for physicians) encountered in caring for patients with Alzheimer's disease and related dementias (ADRD); to review the implications of these policies for the long-term clinical management of the patient with ADRD; and to provide recommendations for promoting appropriate recognition and reimbursement for clinical services provided to ADRD patients. Relevant English-language articles identified from MEDLINE about ADRD prevalence estimates; disease morbidity and mortality; diagnostic coding practices for ADRD; and Medicare, Medicaid, and managed care organization data on diagnostic coding and reimbursement were reviewed. Alzheimer's disease (AD) is grossly undercoded. Few AD cases are recognized at an early stage. Only 13% of a group of patients receiving the AD therapy donepezil had AD as the primary diagnosis, and AD is rarely included as a primary or secondary DRG diagnosis when the condition precipitating admission to the hospital is caused by AD. In addition, AD is often not mentioned on death certificates, although it may be the proximate cause of death. There is only one ICD-9-CM code for AD-331.0-and no clinical modification codes, despite numerous complications that can be directly attributed to AD. Medicare carriers consider ICD-9 codes for senile dementia (290 series) to be mental health codes and pay them at a lower rate than medical codes. DRG coding is biased against recognition of ADRD as an acute, admitting diagnosis. The CPT code system is an impediment to quality of care for ADRD patients because the complex, time-intensive services ADRD patients require are not adequately, if at all, reimbursed. Also, physicians treating significant numbers of AD patients are at greater risk of audit if they submit a high frequency of complex codes. AD is grossly undercoded in acute hospital and outpatient care settings because of failure to diagnose, limitations of the coding system, and reimbursement issues. Such undercoding leads to a lack of recognition of the effect of AD and its complications on clinical care and impedes the development of better care management. We recommend continuing physician education on the importance of early diagnosis and care management of AD and its documentation through appropriate coding, expansion of the current ICD-9-CM codes for AD, more appropriate use of DRG coding for ADRD, recognition of the need for time-intensive services by ADRD patients that result in a higher frequency of use of complex CPT codes, and reimbursement for CPT codes that cover ADRD care management services.

Background and Objectives: Studies on the relationship between Alzheimer's disease (AD) and health care costs have yielded conflicting results. This study analyzed the relationship between co-morbid conditions and health care utilization and costs for patients with AD and estimated costs by stage of disease and receipt of pharmacotherapy., Methods: We conducted a retrospective analysis of administrative data for 1,366 patients with AD and 13,660 age-gender matched controls enrolled in a large Medicare managed care organization (MCO). Co-morbid conditions were based on the diagnostic classifications from the Charlson co-morbidity index. Health care costs and utilization for MCO-covered services for cases were compared to controls. We used presence of complications of AD associated with later-stage disease to classify patients as having earlier- or later-stage AD., Results: After controlling for co-morbid conditions, age, and gender, annual costs were $3,805 higher for AD patients, resulting in excess costs of $5 million to the MCO. For seven of the 10 most prevalent co-morbidities for AD patients, adjusted costs were higher for AD patients compared with controls with the same condition. Higher costs were attributable to higher inpatient and skilled nursing facility costs. Costs for patients classified as earlier-stage AD were 44% higher than controls and significantly higher for eight of 10 co-morbid conditions when compared with controls with the same conditions. Costs for AD patients receiving treatment by a cholinesterase inhibitor were $2,408 lower than AD patients not receiving therapy., Conclusions: Utilization and costs for patients with AD were higher compared to controls and were substantially higher for patients with both AD and co-morbid diseases commonly targeted for disease management. Earlier-stage AD and receipt of pharmacotherapy were associated with lower costs. These findings indicate that better treatment and care management of AD could reduce the costs of co-morbid illnesses commonly suffered by AD patients.

The objective of this study was to estimate the ramifications of donepezil use on the health care costs of a large Medicare managed care plan. Patients with a diagnosis of Alzheimer's disease or related dementia were identified from the claims-and-encounter records of the plan. Costs for 204 patients identified as having Alzheimer's disease and who were receiving donepezil were compared with a control group of 204 patients with Alzheimer's disease who had matching characteristics, but who were not receiving therapy. After controlling for age, gender, pharmacy benefits, comorbid conditions, and complications of dementia, annual costs for medical services and prescription drugs were found to be $3,891 lower for the study group. Costs were $4,192 lower for patients receiving longer-term therapy (> or = 270 day supply of donepezil) and $3,579 lower for patients receiving shorter-term therapy when compared with controls. By improving cognitive and daily functioning, donepezil may lower costs by improving medical management.

In a general population survey (N = 314), 79 percent of respondents stated that they would take a hypothetical genetic test to predict whether they will eventually develop Alzheimer's disease. The proportion fell to 45 percent for a "partially predictive" test (which had a one in ten chance of being incorrect). Inclination to obtain testing was similar across age groups. Respondents were willing to pay $324 for the completely predictive test. Respondents stated that if they tested positive, they would sign advance directives (84 percent), get their finances in order (74 percent), and purchase long-term care insurance (69 percent). Only a third of respondents expressed concern about confidentiality. The results suggest that people value genetic testingfor personal and financial reasons, but they also underscore the need to counsel potential recipients carefully about the accuracy and implications of test information.

This study examined the effect of a fitness program for Medicare MCOs on health status and health care utilization of participants. An evaluation compared outcome measures between high-level and low-level participants of the program. High-level participants scored higher on the Health Outcomes Survey and also had fewer doctor visits during the program period compared with low-level participants. The authors conclude that elderly individuals who participated at the high-level rate in a targeted fitness program maintained or improved health status and had fewer outpatient visits compared with the low-level participants. Medicare MCOs may improve health and manage costs for members by employing similar interventions focusing on functional health through exercise.

Background: The number of patients with Alzheimer's disease (AD) and related dementia treated in managed care organizations (MCOs) is increasing, and this trend is expected to continue. Therefore, it is critical that MCOs develop disease management strategies for this population., Objective: To review the literature on the prevalence, costs, and treatment of AD and related dementia., Study Design: Review of published articles from MEDLINE and peer-reviewed journals., Results: Prevalence of AD and related dementia is approximately 5.7% among those aged 65 and older. Prevalence data from claims-based studies of AD in managed care are lower, ranging from 0.55% to 0.83%. Costs for formal care average $27,672 per patient annually, with long-term care being the most costly component. Annual costs for informal care are estimated to be $10,400 to $34,517 per patient. Additional costs associated with AD include lost wages and productivity of patients and caregivers and costs associated with increased morbidity of caregivers. Donepezil treatment is well tolerated and has been extensively tested and evaluated in clinical settings. Early diagnosis and treatment of AD with donepezil has been shown to slow cognitive decline in AD. Although study findings regarding the cost offsets of donepezil-treated patients to date are mixed, there is a growing body of evidence to support the inclusion of this and other therapies into an MCO's AD treatment armamentarium., Conclusions: It is unlikely that MCOs will escape the increased prevalence and costs associated with AD. Opportunities exist through patient management programs targeted toward early diagnosis, effective use of medications, control of comorbidities, and patient and family support to partially offset these costs while providing quality patient care.

Alzheimer's disease (AD), the leading cause of disability in people older than 75 years of age, has direct and indirect medical costs estimated at $100 billion per year. Yet underdiagnosis, coding, and reimbursement barriers result in most patients with AD receiving inadequate care. The vast majority of managed care organizations (MCOs) still lack formal disease management programs for AD. In several documented studies, the total costs for managing patients with AD increased significantly over age- and comorbidity-matched controls without AD. Importantly, these extra costs include not only nursing home care but also medical claims for inpatient stays, emergency department visits, and outpatient care. The extra costs are especially high in those patients with comorbidities such as diabetes or heart failure. Emerging pharmacoeconomic data indicate potential savings in medical care costs associated with early treatment of AD and the potential cost effectiveness of cholinesterase inhibitors such as donepezil. These studies document that Medicare MCOs are in need of directed efforts to improve medical management for members with AD.

Alzheimer's disease (AD) and dementia are responsible for high levels of excess per-member costs within managed care organizations (MCOs). To deal with anticipated increases in the prevalence of this disease within their populations, MCOs should take steps to integrate and target proven pharmacologic and non-pharmacologic AD treatments. Key areas of AD care improvement include protocol-driven diagnosis, referral, and treatment; education of primary care physicians and caregivers; development of an integrated case management approach; and use of validated measures to assess outcomes. Published evidence-based guidelines are available to assist MCOs in developing clinical protocols for diagnosis and treatment with effective agents such as cholinesterase inhibitors. Because of the opportunity to prevent costly hospitalizations and other complications as a result of medical and behavioral comorbidities, and because of the need for tightly integrated care, a disease management approach for AD may be justified.

Interactions of heparin with intact human thrombospondin-1 (TSP1) and with two heparin-binding fragments of TSP1 were characterized using chemically modified heparins, a vascular heparan sulfate proteoglycan, and a series of heparin oligosaccharides prepared by partial deaminative cleavage. The avidity of TSP1 binding increased with oligosaccharide size, with plateaus at 4 to 6 and at 8 to 10 monosaccharide units. The dependence on oligosaccharide size for binding to the recombinant amino-terminal heparin-binding domain of TSP1 was the same as that of the intact TSP1 molecule but differed from that of a synthetic heparin-binding peptide from the type 1 repeats, suggesting that the interaction between intact TSP1 and heparin is primarily mediated by the amino-terminal domain. Based on activities of chemically modified heparins, binding to TSP1 depended primarily on 2-N- and 6-O-sulfation of glucosamine and to a lesser degree on 2,3-O-sulfation and the carboxyl residues of the uronic acids. In contrast, all of these modifications were required for binding of heparin to the type 1 repeat peptides. Affinity purification of heparin octasaccharides on immobilized TSP1 type 1 repeat peptides revealed a preference for oligosaccharides containing the disaccharide sequence IdoA(2-OSO(3))alpha1-4-GlcNS(6-OSO(3)). Binding of these oligosaccharides to the peptide required the Trp residues. These data demonstrate that the heparin-binding specificities of intact TSP1 and peptides from the type 1 repeats overlap with that of basic fibroblast growth factor (FGF2) and are consistent with the ability of these TSP1-derived molecules to inhibit FGF2-stimulated angiogenesis., (Copyright 2000 Academic Press.)

The progressive loss of social and physical functioning associated with Alzheimer's disease (AD) results in extensive social and economic costs to society. The early diagnosis and treatment of AD may reduce cognitive and behavioral symptoms of this disease and may slow disease progression, thereby alleviating some of these social and economic costs. The Alzheimer's Disease Managed Care Advisory Council, a panel of experts from managed care, academic medicine, and the Los Angeles chapter of the Alzheimer's Association was convened to synthesize current evidence-based recommendations for AD diagnostic and treatment guidelines and to integrate these guidelines for use in MCOs. This paper presents conclusions from this panel and provides an algorithm for the treatment of AD specifically for managed care settings. When combined with other necessary efforts to educate providers, these guidelines should improve the cost-effectiveness and quality of care for individuals with dementia in managed care.

Background: Managed care organizations (MCOs) will have increased responsibility for the care of large numbers of persons with dementia. There are, however, few studies that inform about decisions of healthcare utilization and expenditures for individuals with dementia in managed care., Objectives: To examine in a large MCO whether people diagnosed with dementia have higher healthcare utilization and costs than enrollees without dementia., Design: A retrospective study of medical and prescription claims., Setting: An MCO covering more than 80,000 Medicare enrollees in four geographical locales between January 1, 1996, and March 31, 1998., Subjects: There were 677 paired cases with and without dementia. Controls were selected randomly and matched to cases on age, gender, and region., Measurements: Summed total costs and number of claims accrued during the study period, as well as a breakdown of costs and claims with respect to place of service, were annualized and adjusted for age, gender, and comorbid conditions. Costs and claims were broken down by place of service., Results: Dementia prevalence was 0.83%. Mean total costs were 1.5 times higher for patients with dementia relative to controls ($13,487 vs $9,276, P < .001) when annualized and adjusted for level of comorbidity. Almost 75% of the higher costs among cases were linked to inpatient expenses., Conclusions: Higher costs for individuals with dementia and disproportionate inpatient costs in this MCO parallel patterns among Medicare enrollees in fee-for-service. The high prevalence of dementia among the oldest old coupled with the high costs of dementia care create very significant clinical and financial incentives for managed care plans to improve the care of members suffering from dementia.

Perlecan is a specific proteoglycan that binds to amyloid precursor protein and beta-amyloid peptide, is present within amyloid deposits, and has been implicated in plaque formation. Because plaque formation is associated with local inflammation, we hypothesized that the mechanisms involved in brain inflammatory responses could influence perlecan biosynthesis. To test this hypothesis, we first studied perlecan regulation in mice after inflammation induced by a brain stab wound. Perlecan mRNA and immunoreactivity were both increased 3 days after injury. Interleukin-1alpha (IL-1alpha) is a cytokine induced after injury and plays an important role in inflammation. As such, IL-1alpha may be one of the factors participating in regulating perlecan synthesis. We thus studied perlecan regulation by IL-1alpha, in vivo. Regulation of perlecan mRNA by this cytokine was area-specific, showing up-regulation in hippocampus, whereas in striatum, perlecan mRNA was unchanged. To support this differential regulation of perlecan mRNA by IL-1alpha, basic fibroblast growth factor (bFGF), a growth factor also present in plaques, was studied in parallel. bFGF mRNA did not show any regional difference, being up-regulated in both hippocampus and striatum in vivo. In vitro, both astrocyte and microglia were immunoreactive for perlecan. Moreover, perlecan mRNA was increased in hippocampal glial cultures after IL-1alpha but not in striatal glia. These results show an increase in perlecan biosynthesis after injury and suggest a specific regulation of perlecan mRNA by IL-1alpha, which depends on brain area. Such regulation may have important implications in the understanding of regional brain variations in amyloid plaque formation.

Objective: To examine the effects of medication reviews by primary care physicians on prescriptions written for elderly members of a Medicare managed care organization who were at risk for polypharmacy., Study Design: Prospective study with follow-up survey., Patients and Methods: We conducted a study in 1995 to demonstrate the prevalence of polypharmacy (defined as receiving 5 or more prescription medications during the 3-month study period) among elderly members of our managed care organization. Two years later, elderly members identified as being at risk for polypharmacy were sent a letter encouraging them to schedule a medication review with their primary care physician. Each primary care physician was provided with clinical practice guidelines on polypharmacy and patient-specific medication management reports. Patients and physicians were subsequently mailed a survey to assess the impact of the medication review program on prescribing practices., Results: Of 37,372 elderly members screened, 5737 (15%) were at risk for polypharmacy. Of these, 2615 (46%) responded to the follow-up survey. Of the survey respondents, 1087 (42%) had gone to their primary care physician for a medication review. During the review, 96% of patients discussed their prescription medications and 72% discussed nonprescription medications they were taking. Twenty percent reported that their physician discontinued medications, 29% reported that the physician changed the dose of a medication, and 17% informed their physician about a new prescription or nonprescription medication they were taking. Of the 275 primary care physicians surveyed, 56 (20%) returned the questionnaire. Of these, 61% reported that the medication review program was "very" or "somewhat useful." Thirty-five percent reported discontinuing unnecessary medications, and 23% reported decreasing the frequency of dosing. Overall, 45% of physicians reported making at least one change in their prescribing to a member at risk for polypharmacy., Conclusions: Our program promoting medication reviews between primary care physicians and their elderly patients resulted in significant changes in prescribing by physicians. This type of program is likely to decrease the risk of polypharmacy among older members of a Medicare managed care organization.

In this first part of a two-part article, we review the prevalence of, costs associated with, and treatments for Alzheimer's disease and related dementias, a leading cause of disability in the elderly. New, innovative, and costly drugs to combat dementia are being introduced, causing pharmacy costs to rise. These new drugs, however, may reduce overall medical costs and improve the quality of life of patients with dementia and their caregivers. Issues of cost, excessive service utilization, and quality of life will have significant impact on managed care organizations in the near future as the rapidly aging population experiences significant disability and illness related to dementia. In the second part of this article, we describe the framework for a disease management program for patients with dementia, similar to programs in existence for diabetes and other chronic diseases, that could enable managed care organizations to effectively care for these patients.

In this second part of a review of dementia, we argue that managed care organizations must develop strategies to identify and manage patients with dementia, whose numbers will increase dramatically in the near future. Improved coding and use of validated self-report instruments that include caregivers as information sources could assist in identifying patients with dementia who could benefit from disease management programs. These programs should include population-based screening efforts; the development of practice guidelines; the use of case managers; education of caregivers, case managers, and physicians in issues such as availability of community services, patient/caregiver self-management techniques, and the latest developments in efficacious treatment; and monitoring of care through quality assurance activities. Dementia is a highly prevalent, devastating, and costly chronic illness of the elderly, but it is also eminently manageable. Managed care has the potential to improve the quality of life and care for these patients, while managing the costs.

In traditional geriatric medicine, comprehensive assessment is considered crucial to the care of frail older patients. The principles of geriatric assessment--identifying high-risk patients and targeting them for preventive interventions--are also practiced by managed care organizations (MCOs). Self-reported health surveys and administrative data are two methods used by MCOs to identify members at high risk for adverse health outcomes and functional decline who may benefit from geriatric case management. For a successful partnership with primary care physicians, it is very important that geriatric care managers should be knowledgeable in the principles of geriatric medicine.

We have previously demonstrated that full-length heparin stimulates the synthesis and secretion of beta-amyloid precursor protein (APP) through an amyloidogenic pathway in neuroblastoma cells. In the present study, heparin was chemically depolymerized, and the effect of low-molecular-weight (LMW) heparin on APP secretion was investigated. In contrast to full-length heparin, LMW heparin had no significant effect on APP secretion. However, LMW heparin fragments, especially heparin disaccharides, were able to inhibit efficiently the stimulatory effect of heparin on APP secretion. LMW heparin derivatives also inhibit the binding of heparin to the beta-amyloid peptide (1-28). Using an in vitro model, we further demonstrated the passage of LMW heparin derivatives through the blood-brain barrier. This study suggests that LMW heparin derivatives or analogues may be effective as therapeutic agents to prevent or slow the process of amyloidogenesis in Alzheimer's disease.

In Alzheimer's disease, abnormal processing of the amyloid precursor protein (APP) is thought to play an important role in amyloid deposition. We investigated the effect of heparin, a highly sulfated glycosaminoglycan related to heparan sulfate, on the secretion of the beta-secretase cleavage product of APP (sAPP beta) in a human neuroblastoma cell line. Heparin induced an increase in the secretion of total APP, and an even greater relative increase in the secretion of sAPP beta. The effect on sAPP beta was specific to heparin. These data support the hypothesis that highly sulfated heparan sulfate proteoglycans may promote amyloidogenic pathways of APP metabolism.

Heparan sulfate proteoglycans have pleiotropic functions in the normal vasculature. Autoimmunity to heparan sulfate may play a role in vascular injury. In this study, monoclonal antibody (mb) 28C3-1 to heparan sulfate derived from autoimmune Tight skin (TSK) mice was investigated for its reactivity with endothelial cells. Mb 28C3-1 was previously demonstrated to inhibit the heparin-accelerated formation of antithrombin III-thrombin complexes. In the current studies it is shown that mAb 28C3-1 bound to heparan sulfate proteoglycan with the highest affinity in direct binding solid phase radioimmunoassay. Binding to the heparan sulfate was stronger than binding to the protein core, indicating that the primary epitope of 28C3-1 is the polysaccharide component. Using confocal fluorescent microscopy, mAb 28C3-1 was demonstrated to bind to the endothelial cell surface. Furthermore, treatment of endothelial cells with heparitinase abolished mAb 28C3-1 binding. These studies support the hypothesis that naturally occurring anti-heparan sulfate autoantibodies from autoimmune mice may cause vascular injury by initial interaction with endothelial cell surface heparan sulfate.

Adverse drug reactions and inappropriate prescribing practices are an important cause of hospitalization, morbidity, and mortality in the elderly. This study compares prescribing practices within a Medicare risk contract health maintenance organization (HMO) in 1993 and 1994 with prescribing practices for two nationally representative samples of elderly individuals predominantly receiving medical care within the Medicare fee-for-service sector. Information on prescriptions in the fee-for-service sector came from the 1987 National Medical Expenditures Survey (NMES) and the 1992 Medicare Current Beneficiary Survey (MCBS). A total of 20 drugs were studied; these drugs were deemed inappropriate for the elderly because their risk of causing adverse events exceeded their health benefits, according to a consensus panel of experts in geriatrics and pharmacology. One or more of the 20 potentially inappropriate drugs was prescribed to 11.53% of the Medicare HMO members in 1994. These medications were prescribed significantly less often to HMO members in 1994 than to individuals in the fee-for-service sector, based on information from both the 1987 NMES and the 1992 MCBS. Utilization of unsafe or ineffective medications actually decreased with increasing age in the HMO sample, with lowest rates in individuals over the age of 85. However, no relationship between age and medication use was seen in the NMES study, except for individuals over the age of 90 years. The study data support the conclusion that ineffective or unsafe medications were prescribed less often in the Medicare HMO than in national comparison groups. In fact, for the very old, who are most at risk, the use of these medications was much lower in the Medicare HMO than in the Medicare fee-for-service sector. Nevertheless, in 1994, approximately one of every nine members of this Medicare HMO received at least one such medication. Continued efforts and innovative strategies to further reduce the use of unsafe and ineffective drugs among elderly Medicare HMO members are needed.

Vasculitis is an common clinical feature of systemic lupus erythematosus (SLE) in humans and in animal models of this disease. Humoral autoimmunity against endothelial cells has been previously demonstrated in SLE and other autoimmune disorders, but the precise cell surface antigenic targets involved in the initiation and progression of vascular injury are still essentially unknown. In the current studies, we demonstrate the presence of autoantibodies in the sera of MRL/lpr/lpr mice which bind endothelial cell surface antigens by ELISA and also cause complement-dependent cytotoxicity of these cells. These MRL/lpr/lpr sera induced complement-dependent cleavage and release of 35SO4-labeled material containing primarily cell surface heparan sulfate proteoglycans from these cells, and react with heparin (a glycosaminoglycan related to heparan sulfate) by ELISA and liquid-phase competitive inhibition ELISA. These data indicate that antiendothelial cell autoantibodies present in autoimmune MRL/lpr/lpr mice are directed at least in part against cell surface heparan sulfate proteoglycans. Autoantibodies to cell surface heparan sulfate proteoglycan may play a role in vascular endothelial cell injury in these animals through complement-dependent, autoimmune mechanisms.

The potential long-term benefits of estrogen replacement therapy (ERT) in the prevention of osteoporosis and heart disease have been reasonably well established. However, the favorable effects of ERT on cognitive function and prevention of senile dementia in old age now represents a revitalized area of clinical research. A growing body of experimental evidence has recently provided the neurobiologic basis to support the hypothesis that gonadal hormones such as estrogen have psychologic effects on human brain function and behavior. Studies in women who have undergone surgical menopause have demonstrated that the menopause is associated with subclinical cognitive and affective dysfunction, which is improved by ERT. In addition, a growing body of evidence suggests that estrogen may be an effective therapy for senile dementia in some elderly women. Recent epidemiologic studies have indicated that long-term postmenopausal ERT may prevent late-life cognitive dysfunction in older women. Several clinical trials employing oral estrogen therapy have also observed that some aged women with senile dementia have improved cognitive and affective function after estrogen therapy. Estrogen loss resulting in cognitive disorders, including menopausal cognitive dysfunction and senile dementia in late life, may act via several mechanisms. Estrogen may be an important growth factor for estrogen-responsive neurons. Estrogen therapy may also have substantial neurochemical effects, direct effects on the vasculature, and effects on the generation of free radicals, which may be toxic to neurons. At this time, several important clinical questions need to be answered regarding the role of ERT in the cognitive and affective dysfunctions associated with menopause and senile dementia. Should estrogen be used for menopausal women whose sole complaint is cognitive or affective dysfunction? Does long-term ERT prevent cognitive decline in late life if initiated at the time of menopause? Can ERT improve cognition and affective function in postmenopausal women with Alzheimer's disease, and does estrogen therapy prevent the progression of Alzheimer's disease in these patients? Finally, do the vascular effects of estrogen play a role in the treatment or prevention of both Alzheimer's disease and vascular dementia?

Inflammation and the response to injury may play an important role in the process of amyloidosis in Alzheimer's disease. We investigated the effect of interleukin-1 (IL-1) and nerve growth factor (NGF) on the metabolism of neuroblastoma proteoglycans. IL-1 and NGF increased the net charge and the net secretion of neuroblastoma proteoglycans. NGF also specifically increased the relative amount of cell-associated and secreted heparan sulfate proteoglycans in these cells. We previously demonstrated that neuroblastoma heparan sulfate proteoglycan binds specifically to the amyloid beta-amyloid peptide involved in Alzheimer's disease. Heparan sulfate glycosaminoglycans synthesized by IL-1-stimulated cells demonstrated an increased relative binding affinity for the beta-amyloid peptide. Thus, IL-1 and NGF induce the hypersecretion and hypersulfation of neuroblastoma heparan sulfate proteoglycans which bind beta-amyloid. These studies link the process of inflammation and repair with alterations in the metabolism of heparan sulfate proteoglycans and amyloid formation in Alzheimer's disease and other disorders.

Lactotransferrin is a glycoprotein that specifically binds and transports iron. This protein is also believed to transport other metals such as aluminum. Several lines of evidence indicate that iron and aluminum are involved in the pathogenesis of many dementing diseases. In this context, the analysis of the iron-binding protein distribution in the brains of patients affected by neurodegenerative disorders is of particular interest. In the present study, the distribution of lactotransferrin was analyzed by immunohistochemistry in the cerebral cortex from patients presenting with Alzheimer's disease, Down syndrome, amyotrophic lateral sclerosis/parkinsonism-dementia complex of Guam, sporadic amyotrophic lateral sclerosis, or Pick's disease. The results show that lactotransferrin accumulates in the characteristic lesions of the different pathologic conditions investigated. For instance, in Alzheimer's disease and Guamanian cases, a subpopulation of neurofibrillary tangles was intensely labeled in the hippocampal formation and inferior temporal cortex. Senile plaques and Pick bodies were also consistently labeled. These staining patterns were comparable to those obtained with antibodies to the microtubule-associated protein tau and the amyloid beta A4 protein, although generally fewer neurofibrillary tangles were positive for lactotransferrin than for tau protein. Neuronal cytoplasmic staining with lactotransferrin antibodies, was observed in a subpopulation of pyramidal neurons in normal aging, and was more pronounced in Alzheimer's disease, Guamanian cases, Pick's disease, and particularly in Down syndrome. Lactotransferrin was also strongly associated with Betz cells and other motoneurons in the primary motor cortex of control, Alzheimer's disease, Down syndrome, Guamanian and Pick's disease cases. These same lactotransferrin-immunoreactive motoneurons were severely affected in the cases with amyotrophic lateral sclerosis. It is possible that in these neurodegenerative disorders affected neurons either take up or synthesize lactotransferrin to an abnormally elevated rate. An excessive accumulation of lactotransferrin, as well as transported iron and aluminum, may lead to a cytotoxic effect resulting in the formation of intracellular lesions and neuronal death.

Heparin sulfate proteoglycans are believed to play an important role in amyloidosis as pathologic chaperones. They bind to amyloidogenic proteins and may mediate the deposition and fibrillogenesis of amyloid at specific tissue sites. In the present study, we demonstrate that heparin sulfate glycosaminoglycan and proteoglycan both bind to the beta-amyloid peptide involved in Alzheimer's disease. The interaction of heparan sulfate proteoglycan and glycosaminoglycan can be inhibited by other sulfated compounds such as heparin, dextran sulfate and pentosan polysulfate. These polysaccharides which are currently used clinically, their derivatives or analogs may be effective as therapeutic agents to prevent or slow the progression of amyloidogenesis in Alzheimer's disease or other amyloidogenic disorders.

The Mount Sinai Medical Center's Geriatric Evaluation and Treatment Unit (GETU) is a 16-bed acute care geriatric unit that operates under the Medicare Prospective Payment System (PPS) in an academic medical center environment. The Medicare PPS and the needs of our local health care system have played a considerable role in the development and operation of our inpatient acute care geriatric unit. The GETU provides acute geriatric care and geriatric assessment and is a site for education and clinical research. The GETU serves a targeted group of acutely ill, hospitalized frail elderly with complex, interdisciplinary needs. The multidisciplinary GETU team was financed from generally available and justifiable hospital resources. Geriatric assessment is conducted under the Medicare PPS during the process of acute care without prolonging hospital length of stay. In fact, during the past 6 years, the introduction of geriatric care and assessment programs has been associated with a significant reduction in hospital length of stay and hospital costs for this complex and difficult population. It is our experience that an acute care geriatric unit functioning under traditional Medical Prospective Payment can have the dual effect of enhancing care and reducing hospital costs for the hospitalized frail elderly.

Vascular heparan sulfate proteoglycan (vHSPG) is an important functional component of the microvasculature. Previous studies have demonstrated autoimmunity to vHSPG in systemic lupus erythematosus (SLE). In the current studies, we further investigated the immunospecificity of anti-vHSPG antibodies in SLE sera by enzyme-linked immunoassay (ELISA). In direct binding assays, SLE sera contained IgG antibodies reactive with native vHSPG and with heparan sulfate (HS) glycosaminoglycan in significantly higher titers than controls. Employing purified SLE IgG in liquid-phase competitive immunoinhibition ELISAs, SLE IgG anti-HS antibodies cross-reacted with heparin and DNA, but not with other glycosaminoglycans or anionic phospholipid antigens. Immunochemical studies demonstrated that the immunodominant site on HS recognized by SLE IgG contained 2-O-sulfated uronic acid. Removal of N-sulfated and 6-O-sulfated residues primarily on N-acetyl-glucosamine had no effect on antigenicity, further demonstrating that nonspecific charge interactions which are the result of sulfation do not solely account for the antigenicity of HS. SLE IgG from patients with active SLE was further affinity purified on DNA-cellulose and HS-Sepharose columns for immunospecificity studies. After affinity purification of both anti-DNA and anti-HS antibodies, significant enhancement of direct binding reactivity with HS was noted. In addition, anti-DNA and anti-HS IgG antibody reacted with the cell surface of endothelial cells by a cellular ELISA (CELISA). Immunoinhibition studies of CELISA reactivity confirmed that affinity-purified SLE IgG anti-DNA anti-HS antibody were reactive with endothelial cell surface HS antigens. Furthermore, SLE IgG anti-DNA antibody reactivity with endothelial cells was not reduced by DNase treatment of the cells, but was significantly reduced by heparitinase digestion. Since HS plays an important role in the maintenance of normal anticoagulation on the endothelial cell surface by binding antithrombin III, we investigated the inhibition of heparin-accelerated thrombin-antithrombin III complex formation by SLE IgG. Purified IgG from patients with active SLE, but not from normal controls, inhibited heparin-accelerated formation of TAT complexes. These studies demonstrate the presence of IgG autoantibodies to HS in patients with SLE. Anti-HS antibodies recognize an antigenic site also present in heparin, but not other glycosaminoglycans, bind to the endothelial cell surface, and inhibit the formation of TAT complexes. SLE IgG anti-HS antibodies recognize a sulfated uronic acid epitope containing 2-O-sulfate which is important in certain functions of HS, including antithrombin III binding. Thus, anti-HS antibodies may promote a procoagulant state at the endothelial cell surface.(ABSTRACT TRUNCATED AT 400 WORDS)

Cytokines play an important role in modulating cellular function. The effect of tumor necrosis factor alpha (TNF-alpha) on the metabolism of proteoglycans (PGs) was studied in mouse aortic endothelial cells (MAE). Confluent and exponentially growing cells were labeled with [35S] sulfate and [3H] glycine, and PGs isolated from the secreted, the pericellular, and intracellular pools. TNF-alpha influenced the metabolism of MAE PGs. This effect of TNF-alpha was dependent on the growth state of the cells. Nondividing MAE secrete PGs that have higher net negative charge than PGs from exponentially growing cells. TNF-alpha treatment further increased the net negative charge of PGs secreted from nondividing cells. Treatment of MAE with TNF-alpha caused a substantial decrease in the sulfation of PGs isolated from pericellular pool of nondividing cells, while it had the opposite effect on pericellular PGs isolated from dividing cells. Our results indicate that changes in PGs metabolism induced by TNF-alpha may contribute to the disturbance of vascular endothelial homeostasis associated with vascular injury in a variety of disease states.

Vascular dementia is seen much more often in people at age 85 than in those between the ages of 55 and 75. The differential diagnosis includes Alzheimer's disease and mixed dementia. The classic criteria for vascular dementia--stepwise deterioration and focal neurologic signs--are important, as focal neurologic signs usually don't occur in Alzheimer's disease. Identifying a significant number of points on the Hachinski scale, including hypertension, can help make a diagnosis of vascular disease. For more effective differential diagnosis, CT or MRI can be useful. However, not all clinicians are convinced of the necessity of imaging, as long as stroke risk factors such as hypertension and hyperlipidemia are managed for all older patients.

The exact mechanisms of deposition and accumulation of amyloid in senile plaques and in blood vessels in Alzheimer's disease remain unknown. Heparan sulfate proteoglycans may play an important role in amyloid deposition in Alzheimer's disease. Previous investigations have demonstrated high affinity binding between heparan sulfate proteoglycans and the amyloid precursor, as well as with the A4 peptide. In the current studies, a specific vascular heparan sulfate proteoglycan found in senile plaques bound with high affinity to two amyloid protein precursors (APP695 and APP770). Vascular heparan sulfate proteoglycan also bound the Alzheimer's amyloid A4 peptide, and not other amyloid protein precursor regions studied, with high affinity. Both heparan sulfate glycosaminoglycan chains and chemically deglycosylated vascular heparan sulfate proteoglycan protein core bound to A4. High affinity interactions between vascular heparan sulfate proteoglycan and the A4 peptide may play a role in the process of amyloidogenesis in Alzheimer's disease, by localizing the site of deposition of A4, protecting A4 from further proteolysis, or by promoting aggregation and fibril formation.

Geographically based inpatient geriatric units are an increasingly common organizational approach throughout the world for the care of the hospitalized frail elderly with complex, multidisciplinary acute care needs. The unit provides comprehensive and efficient quality care to these patients by bringing together, in a geographically based unit, specialists from a multiplicity of disciplines to provide needed services in a coordinated manner. To accomplish its goals, the unit employs experts in geriatric medicine, nursing, social work, psychiatry, and other disciplines in a team approach to comprehensive assessment. The education of medical students, medical housestaff, and geriatrics fellows is a critical function of the unit. The unit also serves as a site for research in improving the care of the hospitalized frail elderly.

Vascular dementia is a clinical syndrome of acquired intellectual impairment resulting from brain injury due to a cerebrovascular disorder. It is a complex diagnosis, and diagnostic criteria vary. In community practice, the physician can probably make the diagnosis based on the history and medical examination. CT demonstration of one or more infarcts increases the likelihood of this diagnosis. Hypertension is a major risk factor for vascular dementia. Others include smoking, hyperlipidemia, atrial fibrillation, diabetes, and a sedentary lifestyle. Cerebrovascular disease is an important cause of cognitive decline in older patients. Therefore, it is important to recognize risk factors for stroke and institute measures for prevention.

As in human scleroderma, tight skin (TSK/+) mice develop cutaneous hyperplasia with over-production of extracellular matrix, including collagen and proteoglycans, associated with autoimmunity to a number of autoantigens. The present study investigated the presence of cellular autoimmunity to basement membrane heparan sulfate proteoglycan (HSPG) in diseased TSK/+mice and their nondiseased littermates, pallid mice (+/pa). Lymphocyte proliferative responses to specific HSPG antigens, including intact HSPG, HSPG protein core (P. Core), and the glycosaminoglycan heparan sulfate (HS) were studied. Splenocytes from young TSK and control pallid mice reacted weakly to intact HSPG and HSPG P. Core antigens and did not respond to HS. However, lymphocytes from old TSK mice were reactive with HSPG and P. Core and demonstrated a de novo response to HS. The proliferative response to intact HSPG and HSPG P. Core in TSK mice was T cell dependent, but the response to HS was T cell independent. The T cell-dependent response was mediated by the CD4-positive subset and required the participation of class II major histocompatibility complex molecules. Cellular autoimmunity to HSPG, a critical cell surface and extracellular matrix component, may play a role in the disease suffered by TSK mice. Further studies are necessary to determine the mechanisms which link autoimmunity to HSPG with the pathology seen in TSK mice, particularly the overproduction of extracellular matrix and fibrosis.

Objective: To examine the utility of brief screening instruments for alcoholism and depression in the frail elderly medical outpatient., Design: Cross-sectional examination., Setting: Coffey Geriatric Outpatient Clinic, The Mount Sinai School of Medicine, New York City., Subjects: Convenience sample of 84 consenting male and female outpatients over 62 years of age., Measurements: The Michigan Alcohol Screening Test (MAST), CAGE questionnaire, and the Geriatric Depression Scale (GDS)., Results: Four subjects (5%) scored positive for alcoholism on the MAST, all of whom had been previously identified by the geriatric clinic staff. In contrast, the CAGE only identified 1 (1.4%) alcoholic subject. Thirty-two percent of subjects scored positive for depression on the GDS, yet only one-third of these depressed patients had been previously identified by the geriatric team as depressed. Among the depressed outpatients, 19% were labeled anxious and received anxiolytics from the geriatric medical staff., Conclusions: Whereas brief alcohol screening instruments to detect alcoholism did not augment the geriatrician's clinical assessment, screening for depression with the GDS may be an important adjunct to the identification of depression in geriatric medical patients.

As components of the cell surface and extracellular matrix, heparan sulfate proteoglycans play an important role in the function of most organs, including the vasculature. Autoimmunity to heparan sulfate (HS) glycosaminoglycan epitopes may play a role in tissue injury. Tight skin (TSK) mice suffer a disease resembling scleroderma, an autoimmune disease associated with alterations in the extracellular matrix of the skin and other organs, as well as vascular injury. Studies of autoimmunity to HS were performed in TSK mice employing a solid-phase radioimmunoassay for the detection of anti-HS antibody. An increase in the clonal frequency of hybridomas secreting anti-HS antibody was noted in TSK mice compared to that in control mice. Liquid-phase competitive inhibition specificity studies of IgM and IgG anti-HS monoclonal antibodies demonstrated little cross-reactivity with other glycosaminoglycans. Some cross-reactivity, albeit at lower affinity, with phosphorylated antigens including DNA, cardiolipin, and RNA polymerase were noted. Negatively charged sulfate groups and carboxyl groups played a role in the immunodominant site. Monoclonal antibodies to HS inhibited the binding of HS to antithrombin III and the formation of thrombin-antithrombin III complexes. These results demonstrate autoimmunity to HS in TSK mice. The results also indicate that HS is a high-affinity antigen of pathological significance for anti-DNA and anti-phospholipid antibodies. Thrombosis induced by polyclonal anti-phospholipid antibodies may be mediated by a subset of these antibodies with high affinity for HS. Anti-HS antibodies may promote a procoagulant state by the blockade of HS binding to antithrombin III, inhibiting the accelerated formation of thrombin-antithrombin III complexes.

Proteoglycans (PGs) may play a fundamental role in all forms of amyloidosis. In Alzheimer's disease, proteoglycans are found deposited in senile plaques and in neurofibrillary tangles. However, the cellular source of these deposited PGs and their role in amyloidosis in Alzheimer's disease is unknown. Proteoglycans were purified from conditioned medium of human neuroblastoma cells (SKNSH-SY 5Y). Two species of proteoglycans were identified by enzyme susceptibility including a heparan sulfate proteoglycan and a dermatan sulfate proteoglycan. A monoclonal antibody to the protein core of a vascular basement membrane heparan sulfate proteoglycan found in senile plaques in Alzheimer's disease cross-reacted with the proteoglycans secreted by human neuroblastoma cells. Binding between 35SO4-labelled neuroblastoma proteoglycans and the Alzheimer amyloid (A4) peptide was demonstrated by affinity chromatography. Specificity studies demonstrated that binding of human neuroblastoma proteoglycans to the amyloid peptide was specific for a heparan sulfate glycosaminoglycan, with some binding to a dermatan sulfate proteoglycan. Binding to A4 was also demonstrated by a chemically deglycosylated protein core preparation. No significant binding of neuroblastoma proteoglycans was found to two other basic peptides derived from the extracellular domain of the beta-amyloid precursor, demonstrating the specificity of proteoglycan binding to the A4 peptide. Human neuroblastoma proteoglycans may bind to the-Alzheimer amyloid A4 peptide in a region with a heparin binding consensus sequence [VHHQKL] which also contains the cleavage site of the beta-amyloid precursor protein. Neuronal proteoglycans may either regulate the secretion of the amyloid protein precursor or modify the binding of the amyloid protein precursor to other cellular adhesion molecules. Alterations in this binding may be related to the pathogenesis of amyloid deposition in Alzheimer's disease.

In the very old, there is an increased prevalence of immunologically mediated vascular disease. Vascular heparan sulfate proteoglycan (vHSPG) is a molecule which plays an important structural and functional role in the vasculature. Autoimmunity to vHSPG may play a role in the pathogenesis of vascular disease. The presence of autoantibodies to vHSPG was investigated in sera from aged nursing home patients who have a high prevalence of vascular disease. The results showed an association of the presence of autoantibodies to vHSPG in the sera from patients in this aged population with vascular disease, particularly cerebrovascular disease, renal disease and diabetes. In addition, autoantibodies to vHSPG protein core were associated with cerebrovascular disease in this frail elderly population. These studies support the hypothesis that autoimmunity may play a role in vascular disease in the aged.

Although common among the hospitalized frail elderly, malnutrition is often unrecognized by clinicians, and its identification is fought with difficulty due to inadequate nutritional assessment methods and standards. This study compared the use of percent ideal body weight (%IBW) and anthropometry in the assessment of malnutrition in the hospitalized frail elderly. Approximaty 45% of patients studied had at least two anthropometric measurements below the 5th percentile, a level reflecting severe malnutrition. However, only 28% of patients were found to be less than 90% IBW, a level reflecting only mild to severe changes in body weight. Serum albumin was below normal (< 35 g/l) in 30% of patients. The total lymphocyte count was below normal (< 1,500 cells/mm3) in 53%, and was severely depressed (< 800 cells/mm3) in 24%. Thus, despite the use of stringent anthropometric criteria indicating severe malnutrition, anthropometry appeared more sensitive than %IBW as a measure of malnutrition in the hospitalized frail elderly. Furthermore, acute illness causes changes in commonly employed blood measures which make them unreliable in the assessment of malnutrition in this population. Anthropometry may prove to be the most stable, easily performed, and sensitive measure of malnutrition in the hospitalized frail elderly. However, further studies are clearly needed, including the development of appropriate anthropometric reference standards for the very old, a population that commonly suffers malnutrition.

Vascular heparan sulfate proteoglycan (vHSPG) has an important role in the normal vasculature, including hemostasis, lipolysis and other vascular functions. These functions are mediated by both the glycosaminoglycan and protein core moieties of vHSPG. Autoimmunity to vHSPG has been demonstrated to play a role in vascular injury in animal models, and is present in patients with autoimmune vascular disease. However, most previous studies of human autoimmunity to vHSPG have only investigated heparan sulfate glycosaminoglycan epitopes. In the current investigations, autoantibodies to the protein core of vHSPG in sera from patients with systemic lupus erythematosus (SLE) were investigated. vHSPG protein core was prepared by chemical deglycosylation. Competitive immunoinhibition ELISA and immunoblotting immunoassays were established employing monoclonal antibodies to vHSPG protein core. SLE sera were demonstrated to contain IgG autoantibodies reactive with the vHSPG protein core by immunoblotting. Human autoantibodies to vHSPG protein core were not inhibited by heparan sulfate confirming their protein core reactivity. Competitive immunoinhibition studies employing a solid phase radioimmunoassay also confirmed the reactivity of human sera with vHPSG protein core. By ELISA, a significant increase in the occurrence of anti-vHSPG protein core antibodies was noted in SLE sera. While most previous investigations have demonstrated autoimmunity to heparan sulfate, the presence of IgG autoantibodies to vHSPG protein core demonstrates that the entire vHSPG proteoglycan is the target of autoimmunity in SLE.

Peptides representing potential antigenic regions of the NC-1 and 7-S domains of the human alpha 1 and alpha 2, and bovine alpha 3 chains of type IV collagen were synthesized either chemically or by the recombinant DNA technique and tested by ELISA using antibodies raised in rabbits against the whole type IV collagen or the NC-1 domain. Sera from patients with Goodpasture syndrome (GP) or with acute poststreptococcal glomerulonephritis (APSGN) were also tested. The location of antigenic determinants was predicted from the primary and secondary structure of the chains, that is, aromaticity, hydrophilicity and presence of beta-turns. All synthetic peptides reacted with the antiserum to type IV collagen (anti-Col IV). Whereas all peptides arising from the NC-1 domain reacted with anti-NC-1, intact 7-S or peptides of the alpha 1 or alpha 2 chain of the 7-S domain did not react. However intact 7-S reacted with anti-Col IV. Two synthetic peptides from the NC-1 domain of alpha 1, (a.a. 71-90 and a.a. 176-190), one from the alpha 2 (a.a. 70-83) and four from the alpha 3 chain (a.a. 72-89, a.a. 104-117, a.a. 133-145, a.a. 185-203) reacted with anti-NC-1 and anti-COL IV. The above peptides, except alpha 3 (72-89) and alpha 3 (185-203), were tested and found to be reactive with sera from patients with GP.(ABSTRACT TRUNCATED AT 250 WORDS)

Thrombospondin is part of a family of adhesive glycoproteins and is involved in a number of physiologic processes such as angiogenesis and neurite outgrowth. Immunohistochemical localization of thrombospondin in normal human brains was investigated in the hippocampus and inferior temporal cortex. Two antibodies (one polyclonal and one monoclonal) against thrombospondin-labeled microvessels, glial cells, and a subpopulation of pyramidal neurons. The distribution of thrombospondin staining in patients with Alzheimer's disease was found to be comparable to control subjects. However, in patients with Alzheimer's disease a subset of pyramidal neurons that may be vulnerable in Alzheimer's disease exhibited decreased staining. This decrease in the intensity of labeling might constitute a marker for a neuronal population prone to early degeneration. In addition, thrombospondin staining was demonstrated in senile plaques in Alzheimer's disease. These results suggest that thrombospondin may be involved in the process of neuronal degeneration and senile plaque formation.

Treatment of dementia costs billions of dollars in long-term care and community services every year. Dementia also burdens the acute care system and may contribute to financial problems for hospitals serving large numbers of demented elderly. In a specialized geriatric medical unit devoted to acute care of the frail elderly, Alzheimer's disease and vascular and mixed dementias afflicted 63% of inpatients and were associated with excess consumption of nursing resources, complications of treatment, nosocomial infections, lengthy hospitalizations, and financial losses to the hospital. Due in part to the effects of dementia on mobility, continence, and nutrition, demented patients suffered more frequently from life-threatening infections, sepsis, iatrogenic disease, and prolonged hospital stays. Hospital losses were 75% higher for demented patients than for nondemented patients. Dementia affected the majority of acute care patients in this study. However, it was rarely coded as an admitting diagnosis, even though it may have been the proximate cause of the medical morbidity which led to the acute hospitalization. In addition, despite the significant impact of dementia on the hospital course and costs, it was a factor in hospital reimbursement in less than one third of cases. The results indicate that dementia was not considered to be an acute diagnosis, nor was it recognized as a complex medical illness. The impact of dementia on acute hospitalization, including the mechanisms by which dementia prolongs the hospital stay, requires further investigation.

A prospective pilot study compared the Neurobehavioral Cognitive Status Examination (NCSE) to the Folstein Mini-Mental State Examination (MMSE) to determine the usefulness of the NCSE as a cognitive screen in a geriatric inpatient population. All patients directly admitted to the geriatric evaluation and treatment unit (GETU) of a university teaching hospital over a two-and-a-half-month period were eligible for the study, in which 42% participated. Within 72 hours of admission, patients were given the MMSE and the NCSE in a nonrandom order by a trained psychologist and a structured interview by a psychiatrist. The ability of the NCSE to detect global cognitive impairment was compared to the MMSE and psychiatrist's assessment. Differences in sensitivity were examined by discordant pair analysis. The psychiatrist's determination of the presence of cognitive impairment was used as the criterion standard. Comparisons of the MMSE and NCSE, respectively, revealed the following: sensitivity 83% versus 100%; specificity 78% versus 11%; positive predictive value 83% versus 43%; and negative predictive value 78% versus 100%. Seven patients who were cognitively impaired by the NCSE were not impaired by the MMSE (p less than 0.05 by discordant pair analysis). The time of administration for the two tests was significantly shorter for the MMSE (14.75 +/- 5.7 minutes) than for the NCSE (38.9 +/- 12.9 minutes). The NCSE was found to be more sensitive than the MMSE in detecting cognitive impairment among geriatric inpatients, but its specificity and positive predictive values were lower. Beyond this pilot study, additional work examining the utility of the NCSE in other geriatric settings and for different purposes (e.g., as part of comprehensive assessment) needs to be performed.