Analysis of the c-FOS gene on chromosome 14 and the promoter of the amyloid precursor protein gene in familial Alzheimer's disease.

The c-FOS gene product, a putative transacting transcriptional regulator of the amyloid precursor protein (APP) gene, is a candidate locus for the familial Alzheimer's disease (FAD) mutation on chromosome 14 (FAD14). In light of this functional relationship, we investigated the nucleotide sequence and segregation of c-FOS and the nucleotide sequence of the 5' APP promoter. Single-stranded conformational polymorphisms (SSCPs) in the c-FOS gene revealed that c-FOS closely cosegregates with the FAD14 gene but does not show allelic association with FAD. A conservative third-position T-->C mutation was demonstrated in exon 2 (codon 84) of c-FOS, and a C-->G substitution was detected at -209 bp in the 5' promoter of APP. Neither were unique to FAD and are unlikely to be pathogenic or secondary modifiers of the FAD phenotype. We conclude that the c-FOS open reading frame is probably not the site of the FAD14 locus, but we cannot exclude the existence of modifier loci on chromosome 21.

Studies of activated microglial cells and macrophages using Alzheimer's disease cerebrospinal fluid in adult rats with experimentally induced lesions.

Previous investigations have shown that cerebrospinal fluid from Alzheimer's disease patients contains antibodies that recognize the amoeboid microglia--a nascent and active form of microglia in the developing rat brain [McRae et al. (1991) Neuroscience 41, 739-752]. The present study extended this to show that the same cerebrospinal fluid from Alzheimer's disease patients also labeled the activated microglia and macrophages induced experimentally in adult central nervous system. Thus, in the spinal cord, activated microglia were elicited following the destruction of the motor neurons by the toxic lectin, Ricinus communis agglutinin, injected into the sciatic nerve. The activated microglia which were closely associated with the soma of the degenerating neurons were intensely immunostained with the cerebrospinal fluid from Alzheimer's disease patients. The labeling pattern was comparable to some known monoclonal antibodies including OX-42, OX-18 and OX-6 that mark microglia. The microglia cells on the contralateral normal side remained unstained. In the cerebrum, activated microglia and neural macrophages were induced following an epidural application of the excitotoxin, kainic acid or cryolesion. Immunoelectron microscopy of these cells showed that the immunoreactivity was localized at the plasma membrane and its derivatives suggesting that these are the sites where the antigens are associated. The results obtained in this investigation suggest that these experimental models may be a means to gain further insight to antigens recognized by antibodies in the cerebrospinal fluid of Alzheimer's disease patients.

Familial Alzheimer disease: a large, multigeneration German kindred.

A German family with 21 members affected by Alzheimer disease (AD) was studied clinically and genetically. The diagnosis was histologically verified in three affected family members. Ancestors were traced through seven generations to a couple residing in East-Westfalia during the middle of the 19th century. Dementia was often accompanied by extrapyramidal features and myoclonus. No cases of Down syndrome or hematologic malignancy occurred in this family. Clinical manifestations, temporal progression, neurological testing, and neuropathological features do not differ from the more common sporadic form of AD. The inheritance pattern is most consistent with autosomal-dominant transmission.

Decreased DNA repair in familial Alzheimer's disease.

Alterations in the capacity of a cell to repair DNA lesions play an important role in a number of human diseases. We and others have demonstrated defective DNA repair of alkylation damage in cells from patients with Alzheimer's disease. It has been hypothesized that this defect is related to the cause of Alzheimer's disease and results in the accumulation of lesions in the central nervous system neurons. One prediction of this hypothesis is that in dominantly inherited Alzheimer's disease, the repair defect will be present in half of the offspring of affected patients long before they develop symptoms of the disease. In order to test the hypothesis that decreased DNA repair is responsible for familial Alzheimer's disease and their at-risk offspring we have studied DNA repair in these individuals after exposure of lymphoblasts to alkylating agents. Our results indicate that cell lines from affected patients repair significantly less damage in 3 h than cell lines from healthy controls. A small number of at-risk individuals were also studied and some of these had lower levels of repair, although more cell lines from individuals in this group must be studied. These findings provide further support for defective DNA repair playing a role in the pathogenesis of Alzheimer's disease.

Changes in blood pressure and plasma noradrenaline in short-term hypothyroidism.

Thirteen patients who had undergone thyroidectomy for thyroid cancer stopped thyroid hormone replacement prior to follow-up radioactive iodine scans. Thyroxine was replaced by triiodothyronine (T3) for 4 weeks and T3 was stopped 2 weeks before the scan and 16 to 19 days before blood pressure measurement and venipuncture for obtaining plasma noradrenaline samples. During this time, a small but significant decrease in systolic blood pressure occurred, both supine and standing, while the corresponding plasma noradrenaline levels increased significantly. These findings indicate that the acute cardiovascular effect of brief thyroid hormone withdrawal is a decrease in blood pressure rather than the increase often observed in chronic hypothyroidism, and that plasma noradrenaline levels may increase much sooner than previously reported after onset of hypothyroidism.

Parkinson's disease and Alzheimer's disease: hypersensitivity to X rays in cultured cell lines.

Fibroblast and/or lymphoblastoid lines from patients with several inherited primary neuronal degenerations are hypersensitive to DNA-damaging agents. Therefore, lymphoblastoid lines were irradiated from patients with sporadic Parkinson's disease (PD), Alzheimer's disease, and amyotrophic lateral sclerosis. The mean survival values of the eight Parkinson's disease and of the six Alzheimer's disease lines, but not of the five amyotrophic lateral sclerosis lines, were less than that of the 28 normal lines. Our results with Parkinson's disease and Alzheimer's disease cells can be explained by a genetic defect arising as a somatic mutation during embryogenesis, causing defective repair of the X-ray type of DNA damage. Such a DNA repair defect could cause an abnormal accumulation of spontaneously occurring DNA damage in Parkinson's disease and Alzheimer's disease neurons in vivo, resulting in their premature death.

Alpha-adrenergic receptors in orthostatic hypotension syndromes.

Alpha-adrenergic receptor function was measured in platelets from patients with orthostatic hypotension and normotensive controls. Patients with idiopathic orthostatic hypotension (IOH) or multiple system atrophy (MSA) had more alpha-receptors than controls. Patients with IOH, but not MSA, produced less prostaglandin E1 (PGE1)-stimulated cyclic AMP (cAMP) than controls. Patients with sympathotonic orthostatic hypotension (SOH) were similar to controls in receptor number and cAMP production. The percent norepinephrine (NE) inhibition of PGE1-stimulated cAMP production was similar in patients and controls. An increase in alpha-receptor number may result from decreased peripheral NE secretion in IOH and MSA. Increased alpha-receptor number and decreased cAMP production, which accompany essential hypertension, may contribute to the supine hypertension of IOH, and an increase in alpha-receptor number may contribute to the supine hypertension of MSA. SOH patients appear to have no abnormalities of alpha-receptor function.

Evidence that lack of deoxyribonucleic acid repair causes death of neurons in xeroderma pigmentosum.

Xeroderma pigmentosum (XP) is an autosomal recessive disorder with hypersensitivity to the lethal effects of ultraviolet radiation caused by inherited defects in deoxyribonucleic acid (DNA) repair processes. Some patients with XP develop a primary neuronal degeneration which has been thought to result from unrepaired damage in neuronal DNA. Five years ago we reported that cultured skin fibroblasts from a 12-year-old girl with XP, who then had only one major neurological abnormality of the disease, had a sensitivity to ultraviolet radiation intermediate between that of XP patients with numerous neurological abnormalities and those with none. Recent neurological studies reveal that she has a slowly but progressively developing sensorineural deafness as well as cerebellar and motor dysfunction typical of XP. The results support the postulate that defective DNA repair is associated with premature neuron death.

A family with histologically confirmed Alzheimer's disease.

A Canadian family comprising 51 members affected with Alzheimer's disease was evaluated clinically, histologically, and genetically. Ancestors were traced through eight generations, and 51 members were examined at the National Institute of Mental Health, Bethesda, Md. The pedigree is consistent with autosomal dominant inheritance. The effect of interrelatedness among some parents of affected individuals is unknown. In contrast to other studies, there was not an increased incidence of Down's syndrome, hematologic malignancy, or preponderance of affected females.

Relation between plasma and cerebrospinal fluid levels of 3-methoxy-4-hydroxyphenylglycol.

Concentrations of free 3-methoxy-4-hydroxyphenylglycol in the plasma and cerebrospinal fluid are highly correlated, but concentrations in the cerebrospinal fluid are always higher than those in plasma, even when large amounts of the catecholamine metabolite are derived from a tumor of the adrenal medulla. This is explained by considering the plasma and cerebrospinal fluid as a two-compartment system in which the rate constants for entry into and exit from the cerebrospinal fluid compartment are similar. 3-Methoxy-4-hydroxyphenylglycol that is synthesized, but not catabolized, in the central nervous system maintains cerebrospinal fluid levels at an increment over those in plasma. This increment can be used to provide the best available index of formation of 3-methoxy-4-hydroxyphenylglycol in the central nervous system.

Lymphocyte proteins in Huntington's disease: quantitative analysis by use of two-dimensional electrophoresis and computerized densitometry.

We used quantitative two-dimensional electrophoresis to study lymphocyte proteins in Hungtington's disease. Three hundred and six polypeptides from 14C-labeled, phytohemagglutinin-stimulated lymphocytes were measured for variation in relative spot density and 186 for variation in spot position by use of a computer program requiring operator interaction. Each polypeptide was measured in a total of 30 electrophoretograms from 28 individuals, including 13 with Huntington's disease, 2 at risk for it, and 13 controls. The study included two sets of identical twins and, as neurological controls, individuals with neurofibromatosis, Alzheimer's disease, or Shy-Drager syndrome. Seven protein polymorphisms were identified among the 186 most dense polypeptides of each gel, corresponding to a minimum average heterozygosity of 1.4%. Stringent criteria were used to define polymorphic proteins, including observation of at least one individual with each of two homozygous phenotypes and one with the heterozygous phenotype, demonstration of the expected gene dosage relationship by quantitative densitometry, consistency with genetic relationships, and reproducibility. One polymorphic protein showed three electrophoretically variant alleles. Our identification of seven polymorphisms among the 186 proteins measured on a single electrophoretogram illustrates the potential of this technique for performing linkage analysis in diseases of genetic origin. However, we observed no quantitative or positional protein variations that were characteristic of (i.e. specific for) Huntington's disease.

Pancreatic polypeptide responses to hypoglycemia in chronic autonomic failure.

Pancreatic polypeptide (PP) and catecholamine responses to insulin-induced hypoglycemia have been measured in 15 patients with neurogenic orthostatic hypotension. Eight of the patients had idiopathic orthostatic hypotension, and 7 had multiple system atrophy, a condition characterized by the presence of central nervous system lesions in addition to the orthostatic hypotension common to both diseases. Eleven healthy subjects exhibited rapid and substantial elevations in plasma epinephrine, norepinephrine, and PP concentrations in response to insulin hypoglycemia. In contrast, patients with neurogenic orthostatic hypotension exhibited impaired catecholamine and PP responses to insulin hypoglycemia. There was no correlation between the catecholamine and PP responses in either the normal subjects or the patients, suggesting that PP release during hypoglycemia is independent of the sympathoadrenal medullary response. As PP release in response to insulin hypoglycemia is abolished by truncal vagotomy and unaffected by splanchnic nerve section, our results suggest that patients with chronic autonomic failure may have a diffuse autonomic dysfunction involving the parasympathetic as well as the sympathetic nervous system.