New directions in neuroprotection: basic mechanisms, molecular targets and treatment strategies.
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Biomedical subjects
H M Fillit
Publications and source records attributed to H M Fillit.
Prevalence, costs, and treatment of Alzheimer's disease and related dementia: a managed care perspective.
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.
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Specificities of heparin-binding sites from the amino-terminus and type 1 repeats of thrombospondin-1.
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.
Amino Acid Sequence↗
Impact of donepezil on caregiving burden for patients with Alzheimer's disease.
Comprehensive Alzheimer's disease (AD) treatment should address caregiver well-being. We predicted that caregiver burden would be lower among caregivers of AD patients who received donepezil relative to caregivers of patients not treated with donepezil. A self-administered, nationwide survey of AD caregivers was used to match caregivers of patients treated with donepezil (n = 274) to caregivers of patients not treated with donepezil (n = 274). The Caregiver Burden Scale measured time demands and distress linked to commonly performed caregiving tasks. Respondents were three-quarters female, with an average age of 60 years. Results demonstrated that donepezil caregivers reported significantly lower scores on difficulty of caregiving. This difference remained when statistical controls for multiple patient and caregiver variables were imposed. However, selection factors must be recognized as a possible explanation for differences. The groups reported no difference on the time-demand subscale. In conclusion, better management of AD symptoms through donepezil treatment may reduce the burden of caregiving, providing physicians with a pharmacologic approach to improving quality of life for AD patients and their families.
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The pharmacoeconomics of Alzheimer's disease.
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.
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Managed care decisions in Alzheimer's disease.
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.
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Polypharmacy management in Medicare managed care: changes in prescribing by primary care physicians resulting from a program promoting medication reviews.
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.
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How the principles of geriatric assessment are shaping managed care.
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.
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Heparin promotes beta-secretase cleavage of the Alzheimer's amyloid precursor protein.
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.
Alzheimer Disease↗
Monoclonal antibody to heparan sulfate from autoimmune tight skin (TSK) mice binds to the endothelial cell surface.
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.
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Interleukin-1 and nerve growth factor induce hypersecretion and hypersulfation of neuroblastoma proteoglycans which bind beta-amyloid.
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.
Amyloid beta-Peptides↗
The iron-binding protein lactotransferrin is present in pathologic lesions in a variety of neurodegenerative disorders: a comparative immunohistochemical analysis.
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.
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Pathological alterations of the cerebral microvasculature in Alzheimer's disease and related dementing disorders.
Alterations of the cerebral microvasculature have been reported in aging and in neurodegenerative disorders such as Alzheimer's disease. However, the exact role of microvascular alterations in the pathogenesis of neurodegeneration remains unknown. In the present report, the cerebral cortex microvasculature was studied by immunohistochemistry using a monoclonal antibody against vascular heparan sulfate proteoglycan protein core in normal aging controls. Alzheimer's disease, Down syndrome, Guam amyotrophic lateral sclerosis/parkinsonian dementia complex, Pick's disease and dementia pugilistica. In all dementing illnesses, increased microvascular pathology was evident compared to normal controls. Decreased microvascular density and numerous atrophic vessels were the primary abnormalities observed in all dementing disorders. These microvascular abnormalities demonstrated regional and laminar selectivity, and were primarily found in layers III and V of frontal and temporal cortex. Quantitative analysis employing computer-assisted microscopy demonstrated that the decrease in microvascular density in Alzheimer's disease was statistically significant compared to age-matched controls. In addition, extracellular heparan sulfate proteoglycan deposits were observed which colocalized with thioflavine S-positive senile plaques in Alzheimer's disease, Down syndrome and selected Guam dementia cases. In some cases, heparan sulfate proteoglycan was seen in senile plaques that appeared to be diffuse or primitive plaques that stained weakly with thioflavine. Heparan sulfate proteoglycan-containing neurons were also observed in Alzheimer's disease, as well as in Down syndrome and Guam cases. Glial staining for heparan sulfate proteoglycan was never observed. Our data support previous observations that microvascular pathology is found in aging and in Alzheimer's disease. The changes in Alzheimer's disease exceed those found in normal aging controls. We also found microvascular pathology in all other dementing disorders studied. Our studies further demonstrated that the microvascular pathology displays regional and laminar patterns which parallel patterns of neuronal loss. Finally, we also found that heparan sulfate proteoglycan is present in senile plaques and neurons not only as previously reported in Alzheimer's disease, but also in Down syndrome and Guam cases. Heparan sulfate proteoglycan in senile plaques may be derived from either the degenerating microvasculature or from degenerating neurons.(ABSTRACT TRUNCATED AT 400 WORDS)
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Tumor necrosis factor-alpha alters the metabolism of endothelial cell proteoglycans.
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.
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Binding of vascular heparan sulfate proteoglycan to Alzheimer's amyloid precursor protein is mediated in part by the N-terminal region of A4 peptide.
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.
Alzheimer Disease↗
Immunohistochemical identification of thrombospondin in normal human brain and in Alzheimer's disease.
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.
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Decisions for and against resuscitation in an acute geriatric medicine unit serving the frail elderly.
Recent studies indicate continuing controversy over the appropriateness of intensive care in various clinical settings, particularly for very young and very old patients. We studied decisions regarding cardiopulmonary resuscitation (CPR) and the associated clinical course in an acute geriatric unit serving the frail elderly. Despite multiple acute and chronic conditions, advanced age, and functional impairment, patients overwhelmingly preferred CPR. The patients with do-not-resuscitate (DNR) orders were more functionally dependent, more acutely and chronically ill, and less likely to participate in the decision regarding CPR. The majority of DNR orders were made by surrogates, while the majority of CPR directives were made by the patients themselves. Other forms of acute and supportive care, such as parenteral antibiotics, artificial feeding, and transfusions were not withheld from the DNR patients unless a separate decision to limit a specific treatment was undertaken following consultation between the attending physician and the patient or family. Acuity of illness greater than two SDs above the unit mean and the presence of a surrogate decision maker predicted the majority of DNR orders. Length of stay averaged 28 days for all unit patients, 24 days for patients choosing CPR, and 46 days for patients with DNR orders. The four patients who were resuscitated but died stayed an average of 25 days, while the two survivors of resuscitation stayed 20 and 53 days, respectively. The findings indicate that patients and their families considered appropriate clinical criteria including severity of illness when making their decisions about CPR. Nevertheless, the majority chose to be resuscitated in the event of an arrest. Further studies are needed to explore medical decision making by elderly inpatients and their surrogates and to describe the associated clinical course.
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Optimization of an alcian blue dot-blot assay for the detection of glycosaminoglycans and proteoglycans.
A modification of a method for the detection of proteoglycans on positively charged nylon was adapted for use in a dot-blot assay and improved. Different dot-blot membranes were tested and variations in the Alcian blue staining solution (including pH, critical electrolyte concentration, and ionic strength) were explored. With modifications, we were able to eliminate interferences by other polyanions such as DNA or proteins. We were able to detect glycosaminoglycans and proteoglycans down to the 10 ng range. Furthermore, our assay is compatible with high concentration of urea (up to 7 M) used in classic proteoglycans extraction methods and is a useful tool to monitor the isolation of proteoglycans by anion exchange and gel filtration chromatography. It is technically easier, faster, more sensitive, and more specific than previously published methods and can be adaptated as a quantitative assay using a scanning densitometer with a linear range of detection from 10 to 100 ng of glycosaminoglycans.
Alcian Blue↗