The development of new therapeutics for Alzheimer's disease.

Existing treatments for Alzheimer's disease (AD) fail to address the underlying pathology of the disease; they merely provide short-lived symptomatic relief. Consequently, the progression of AD is unrelenting, leading to a continual decrease in cognitive abilities. Recent advances in understanding the genetic factors that predispose to AD, as well as in biomarker development, have brought with them the promise of earlier and more reliable diagnosis of this disease. As improvements continue to be made in these areas, the shortcomings of current AD treatments appear all the more acute because opportunities for early intervention are hindered by a lack of "curative" or even disease-modifying drugs. This State of the Art report reviews existing AD therapeutics and highlights recent progress made in the design and development of drugs that are aimed at disrupting AD disease progression by inhibition of the protein misfolding of ß-amyloid (Aß) into neurotoxic oligomeric aggregates.

Femur lengthening with a vascularized tibia bone flap.

A vascularized tibial bone flap based on a single nutrient vessel has been previously proposed for use in long-bone reconstruction. While the routine use of the tibia for donor bone tissue is precluded by its essential weight-bearing function, in select cases it provides a useful alternative to standard donor bone sources. Cadaver dissection was performed to confirm the endosteal and periosteal vascular anatomy of the tibia. The presence of a consistent nutrient vessel was confirmed. Selective dye injection demonstrated a dual cortical blood supply based on both the endosteal nutrient vessel and multiple periosteal perforator vessels. Inclusion of both vascular supplies maximizes perfusion of bone and periosteum, thus potentially optimizing bone healing and osseous union. Based on these findings, the vascularized tibial bone flap was applied to a clinical case. A 45-year-old male veteran sustained a right proximal femur fracture in a motor vehicle accident. Multiple attempts at fusion with open reduction, internal fixation, grafting, and nonvascularized fibular onlay strut with cerclage wires were all unsuccessful. The patient presented with a chronic right femur nonunion with painful pseudoarthrosis; frozen knee joint; and an internally rotated, 20.3-cm shortened, nonfunctional lower limb. Femur length proximal to the nonunion was less than 15 cm. A maximum amputation stump length is recommended for optimal prosthetic function. A 15-cm pedicled tibial bone flap based on the posterior tibial endosteal and periosteal vascular supply was reversed and plated to the proximal femur to provide a stump of adequate length to optimize prosthetic fitting and function. The tibia is essential for normal weight-bearing, but in select cases may be sacrificed for use in long-bone reconstruction. Expanded use of tibial vascularized allografts in long-bone reconstruction may be made possible following future development of effective and safe immunosuppressive therapy. Transfer based on the posterior tibial pedicle, which includes the endosteal nutrient vessel as well as the periosteal supply via the tibialis posterior muscle, maximizes bone perfusion. The pedicle is of sufficient length to be used for positioning the tibia in the thigh or for free transfer to distant sites.

Amyloid A4 protein and its precursor in Down's syndrome and Alzheimer's disease.

In patients with Alzheimer's disease, amyloid fibrils that are aggregates of A4 protein subunits are deposited in the brain. A similar process occurs at an earlier age in persons with Down's syndrome. To investigate the deposition of amyloid in these diseases, we used a radioimmunoassay to measure levels of the amyloid precursor (PreA4) in the serum of 17 patients with Down's syndrome, 15 patients with Alzheimer's disease, and 33 normal elderly controls. The mean (+/- SD) concentration of serum PreA4 was increased 1.5-fold in patients with Down's syndrome (2.49 +/- 1.13 nmol per liter) as compared with that in controls (1.68 +/- 0.49 nmol per liter; P less than 0.007); the levels in patients with Alzheimer's disease were similar to those in controls (1.83 +/- 0.78; P less than 0.98). We also found that the concentration of PreA4 in the brain tissue of two adults with Down's syndrome (100 and 190 pmol per gram) was higher than that in the brain tissue of either 26 patients with Alzheimer's disease (64.4 +/- 17.3 pmol per gram) or 17 elderly controls with neurologic disease (68.5 +/- 26.3 pmol per gram). Immunocytochemical studies of brain tissue from 26 patients with Down's syndrome showed that the deposition of A4 protein amyloid began in these patients approximately 50 years earlier than it began in 127 normal aging subjects studied previously, although the rate of deposition was the same. We conclude that, since the gene for PreA4 is on the long arm of chromosome 21, which is present in triplicate in Down's syndrome, overexpression of this gene may lead to increased levels of PreA4 and amyloid deposition in Down's syndrome. However, since increased levels of PreA4 are not present in Alzheimer's disease, additional factors must account for the amyloid deposition in that disorder.

A4 amyloid protein deposition and the diagnosis of Alzheimer's disease: prevalence in aged brains determined by immunocytochemistry compared with conventional neuropathologic techniques.

The histologic diagnosis of Alzheimer's disease (AD) might be aided if a more sensitive marker of aberrant A4 amyloid protein deposition were available. We screened a sample of aged brains, using immunocytochemical methods to detect the A4 protein deposition, and found that, in comparison with conventional histologic techniques (silver impregnation and Congo red), immunocytochemistry is more sensitive and allows an easier demarcation between "normal" and "abnormal." If A4 protein deposition is accepted as a definitive marker for AD, then the age-related prevalence of AD increases dramatically. To what degree these prevalence rates are reflected in clinically detectable impairment of higher cortical function remains to be determined.

Applied ethics for physician assistants. A schematic approach.

Ethical dilemmas in medical decision-making over the past ten years have assumed an unprecedented magnitude of importance. All members of the health care team--including physician assistants--have been drawn into the debate. This development has placed an obligation on PAs to develop skills of ethical analysis in order to make informed contributions. Ethical theory can furnish the basis for formulating a schema that can be used to solve ethical problems.

Amyloid of neurofibrillary tangles of Guamanian parkinsonism-dementia and Alzheimer disease share identical amino acid sequence.

The presence of abundant intraneuronal amyloid in the form of neurofibrillary tangles (NFT) in the brains of Guamanian parkinsonism-dementia patients and the absence of extraneuronal amyloid in the form of vascular amyloid deposits or senile plaques permit the purification of NFT without contamination with extraneuronal amyloid. Thus, we have isolated and determined the amino acid sequence of the polypeptide subunit of the amyloid fibrils of these NFT and describe their ultrastructure. The NFT, which consist of single and paired helical filaments, similar to those of Alzheimer disease, and occasionally triple helical filaments, are composed of multimeric aggregates of a polypeptide of 42 amino acids (A4 protein). The relative molecular mass of the subunit protein, 4.0-4.5 kDa, is the same as the molecular mass of the amyloid of NFT, of the amyloid plaque cores, and of vascular amyloid deposits in Alzheimer disease and Down syndrome; the sequence of 15 amino acid residues at the N-terminus of the amyloid fibrils in the NFT of Guamanian parkinsonism-dementia is identical to that of the amyloid of NFT, amyloid plaque cores, and cerebrovascular deposits in Alzheimer disease and Down syndrome. Furthermore, the heterogeneity, or variation in polypeptide length, of the N-terminus of the amyloid of Guamanian parkinsonism-dementia is the same as in Alzheimer disease and Down syndrome. Our observations indicate that the brain amyloids of these diseases have a common subunit protein, which would also indicate a common pathogenesis.

Stochastic thresholds.

Thresholds have traditionally been represented by a single number; the optimal management of the patient depends on whether his probability of disease is above or below this number. The concept of a threshold as a single number, however, inadequately represents the treatment approach of a group of physicians who do not have all the same threshold or a single physician who is uncertain about the exact value of the threshold. An alternative to a single valued threshold is to consider the threshold as having a probability distribution: for every probability that the patient has the disease there is a probability that the threshold is exceeded. This "stochastic" threshold model contains information about the uncertainty of the threshold estimation. Stochastic thresholds can be useful for testing the sensitivity of a management decision to the patient's probability of disease. They can also be used for comparing the standards of practice of individual physicians or comparing the practice of an individual physician with that of a group.

Neuronal origin of a cerebral amyloid: neurofibrillary tangles of Alzheimer's disease contain the same protein as the amyloid of plaque cores and blood vessels.

The protein component of Alzheimer's disease amyloid [neurofibrillary tangles (NFT), amyloid plaque core and congophilic angiopathy] is an aggregated polypeptide with a subunit mass of 4 kd (the A4 monomer). Based on the degree of N-terminal heterogeneity, the amyloid is first deposited in the neuron, and later in the extracellular space. Using antisera raised against synthetic peptides, we show that the N terminus of A4 (residues 1-11) contains an epitope for neurofibrillary tangles, and the inner region of the molecule (residues 11-23) contains an epitope for plaque cores and vascular amyloid. The non-protein component of the amyloid (aluminum silicate) may form the basis for the deposition or amplification (possible self-replication) of the aggregated amyloid protein. The amyloid of Alzheimer's disease is similar in subunit size, composition but not sequence to the scrapie-associated fibril and its constituent polypeptides. The sequence and composition of NFT are not homologous to those of any of the known components of normal neurofilaments.

Amyloid plaque core protein in Alzheimer disease and Down syndrome.

We have purified and characterized the cerebral amyloid protein that forms the plaque core in Alzheimer disease and in aged individuals with Down syndrome. The protein consists of multimeric aggregates of a polypeptide of about 40 residues (4 kDa). The amino acid composition, molecular mass, and NH2-terminal sequence of this amyloid protein are almost identical to those described for the amyloid deposited in the congophilic angiopathy of Alzheimer disease and Down syndrome, but the plaque core proteins have ragged NH2 termini. The shared 4-kDa subunit indicates a common origin for the amyloids of the plaque core and of the congophilic angiopathy. There are superficial resemblances between the solubility characteristics of the plaque core and some of the properties of scrapie infectivity, but there are no similarities in amino acid sequences between the plaque core and scrapie polypeptides.