Objective: This study compared medical history and findings on initial clinical examination in Native Americans diagnosed with possible or probable Alzheimer's disease (AD) at Native American satellite clinics of the University of Texas (UT) Southwestern Medical Center's Alzheimer's Disease Center with those of Whites diagnosed with probable AD at the UT Southwestern Medical Center's Alzheimer's Disease Clinic. Methods: The information reviewed was contained in the database of the UT Southwestern Alzheimer's Disease Center. Results: In relation to Whites, Native Americans had slightly but significantly greater age at onset of symptoms (71.7 vs. 69.6 years, t = -2.08, p = .04) and equivalent cognitive scores at evaluation (Mini-Mental State Exam score = 17.4 vs. 18.5, t = 0.98, p = .33), despite significantly lower educational level (11.4 vs. 13.4 years, t = 5.63, p < .001). Native Americans were more frequently depressed on examination (22.8% vs. 9.5%, chi(2) = 12, p =.001) and reported diabetes, hypertension, and heart disease significantly more often than did Whites (p < .01 for all), but their survival time after AD diagnosis was similar to that of Whites despite these comorbidities. Conclusions: With the exception of a greater prevalence of depression and cardiovascular risk factors in Native Americans than in Whites, Native Americans had a course of illness similar to that of Whites.

This patient report describes a 68-year-old man with progressive dissolution in motor-speech without concomitant language or cognitive decline, with presumed autosomal dominant inheritance. Motor-speech impairments included marked difficulty in articulating words and in coordinating articulation, phonation, and respiration. Brain imaging results revealed severe focal atrophy of the posterior frontal region extending to the anterior parietal and superior temporal regions bilaterally on structural (MRI) and functional (single photon emission computed tomography) brain imaging studies. The involved neural substrate represented the primary motor cortex, premotor cortex (supplementary motor area), and the postcentral gyrus. Familial history included similar difficulties in his mother, her sister, and his own sister. The isolated involvement of the motor-speech processes alone indicated that this syndrome was distinguishable from progressive aphasia associated with prominent loss of language and from Alzheimer's disease.

Apolipoprotein E (ApoE), postulated to be a major lipid carrier protein in brain, is synthesized and secreted primarily by astrocytes and is involved in brain development and repair. We have analyzed its secretion in primary cultures of older (high passage) slowly dividing and younger (lower passage) rapidly dividing fetal human astrocytes exposed to various inflammatory and anti-inflammatory cytokines, alone and in combination. ApoE secretion was reduced in high passage astrocytes when compared to lower passage astrocytes. A further reduction in ApoE secretion in high passage cells was consistently produced by the combination of cytokines interleukin 1 (Il-1) alpha and beta and interferon (IFN-gamma) cytokines or by the basic fibroblast growth factor (basic-FGF) alone. Epidermal growth factor (EGF) increased ApoE secretion. The combination of these cytokine effects in chronically degenerating brain regions of Alzheimer's disease and other neurodegenerative diseases could reduce the amount of ApoE available for neuronal regeneration. EGF, or agents inducing EGF, could ameliorate these ApoE deficiencies.

The gene for choline acetyltransferase, synthesizing acetylcholine, is induced by several neurotrophic factors. A role for AP-2 in enhancing this transcription and limiting it to neural cells is strongly suggested. Previous studies demonstrated that base pairs +465–727 within the untranslated exon 1 of the porcine gene enhanced the expression of a reporter gene transfected into PC-12 cells. Deletion and mutation experiments indicate that base pairs +465–472 (CCGCGGGG) in the porcine gene, or +307–314 (CCTCGGGG) in the human sequence, were necessary and sufficient for increased gene expression in cholinergic or adrenergic but not liver cells. Constructs containing active sequences, but not inactive mutated sequences, specifically bind nuclear proteins from neuroblastoma cells, but not liver cells, in gel shift experiments. The human and porcine sequences are in agreement with an AP-2 consensus binding sequence, a nuclear transcription factor expressed only in cells derived from the neural crest. Gel shift experiments using recombinant AP-2 confirm this identification. AP-2 antibody further retarded the mobility of these DNA–nuclear extract or DNA–AP-2 complexes. These results support the importance of this AP-2 binding sequence in enhancing and limiting choline acetyltransferase expression in neural cells.

A study of 76 consecutive xenon-133 SPECT studies of regional cerebral blood flow was undertaken to determine the frequency of various patterns of blood flow in cases of clinically diagnosed probable and possible Alzheimer's disease. The reference tomographic section was a slice 6 cm above and parallel to the canthomeatal line. With the use of this technique, the "classic" finding of bilateral temporoparietal (TP) flow reductions as the sole abnormality occurred in only 28% of cases. Bilateral TP reductions accompanied by bilateral or unilateral frontal flow reductions were nearly as common (24%), and other patterns accounted for the other 48% of cases.

An in-gel renaturation method allows the visualization, quantitation, and initial characterization of reiterated DNA restriction fragments (RRFs) without prior possession of their probes. Using this method we analyzed EcoRI restricted DNAs from ten human tumors, paired normal tissues from these patients, ten unpaired tumors, and 26 noncancer patients. Frequent qualitative and quantitative differences in the relative radioactive intensities of all or specific RRFs in the DNA from different individuals have been observed. However, we also report frequent two- to ten-fold alterations in the relative radioactive intensities of several specific RRFs in tumor-control analyses of DNA from the same individual. A 0.65-kb alphoid-like DNA RRF was decreased in six tumors and increased in none. Moreover, a new 1.55-kb RRF was observed in two colon cancer DNAs. Several new RRFs, suggestive of gene amplification, were detected in a neuroblastoma, two of which were also seen in a glioma. These data support frequent qualitative and quantitative alterations of specific reiterated DNA sequences in human cancer when compared with paired controls. This approach will allow the future characterization of specific DNA sequences whose patterns of altered reiteration suggest a role in the emergence of specific malignancies.

The molecular defects responsible for Huntington's disease, the spinocerebellar degenerations, myotonic muscular dystrophy, neurofibromatosis, and tuberous sclerosis, among other major dominant inherited diseases of the nervous system, will be identified using the new techniques of molecular genetics. With synthesized nucleic acid segments complementary to portions of the patient's DNA, known as complementary DNA probes, it will be possible to identify and isolate the mutant gene responsible for a particular disease. These events are referred to as gene cloning. In addition, complex genetic regulatory mechanisms involved in cell differentiation during neuroembryogenesis will be elucidated with the application of these strategies. It is important for the clinician to become familiar with the precision and potential of these new methodologies, because they will soon influence significantly the practice of neurology.

A series of increasingly drug-resistant cell populations were selected and cloned from C-46 murine neuroblastoma with the chemotherapeutic drugs maytansine, vincristine, adriamycin, or Baker's antifol. All clones demonstrated reciprocal cross-resistance to these structurally and functionally diverse drugs and failed to accumulate radiolabeled vincristine, colchicine, or Baker's antifol despite normal drug binding to cell homogenates. Initial isolates of drug-resistant populations were genetically unstable, rapidly reverting to a drug-sensitive phenotype when grown without drug, at 0.05 reversion per cell division. After prolonged growth in drug, this drug-resistant genotype stabilized. Mean chromosome number increased 300% in an initially isolated 20-fold maytansine-resistant clone, which also displayed numerous double-minute chromosomes. Descendants 240-fold more resistant than the parent, also unstable, possessed the wild-type complement of 80 chromosomes, but 45% of these cells possessed 24 double-minute chromosomes per cell; such chromosomes were absent from the drug-sensitive parental clone. Only 1.0 and 1.2 double-minute chromosomes per cell were seen in a 7-fold stably resistant revertant or 1200-fold stably resistant descendants, respectively. Double-minute chromosomes containing amplified genes for the drug target dihydrofolate reductase (tetrahydrofolate dehydrogenase; 5,6,7,8-tetrahydrofolate:NADP+ oxidoreductase, EC 1.5.1.3) have been reported in an unstable methotrexate-resistant R1-A sarcoma. These extrachromosomal gene copies were absent in stably resistant progeny. The presence of similar particles in unstably drug-resistant uptake mutants of neuroblastoma and their diminution in stably resistant descendants supports and extends their possible role in the rapid onset and instability of epigenetic drug resistance in cancer chemotherapy.

Proteins were separated on two-dimensional acrylamide gels obtained from brain samples of patients with Joseph disease, Huntington disease (HD) and multiple sclerosis. Similar protein separations were made from cultured skin fibroblasts of Joseph disease patients. Two major classes of proteins, one with a MW of 50,000 probably representing the glial filamentous acidic protein, or another class with a MW of 40,000 (proteins Jc, Jd, L1 and L2) were increased in the cerebellum of six Joseph disease patients. The same protein species were abnormally increased in HD brains, mainly in the basal ganglia and frontal cortex. These identical classes of protein changes were present in two nosologically separate autosomal dominant neurological disorders, Joseph disease (a spinocerebellar degeneration) and HD (a basal ganglia and cerebral cortical degeneration) and may reflect a biochemical correlation of gliosis and neuronal disease. However, these changes may be evidence that the two diseases are allelic mutations of the same gene. The dominantly inherited spinocerebellar degenerations may result from a primary deficit of glial-neuronal interaction, resulting in neuronal loss but with a compensatory increase in the number of glial cells attempting to provide additional trophic-metabolic support.

Genetic mutants inevitably affect enzyme structure or modify protein metabolism. In some cases a single genetic defect can give rise to a neurological syndrome, but in most cases the genetic basis of neurological disease is far more complex. In this review Roger Rosenberg examines the rapid progress which is being made in identifying the patterns of genetic variation which underlie these problems, and their effective treatment.

Abstract: The relative rates of synthesis and turnover of poly(A)‐containing mRNAs were determined in the S‐20 (cholinergic) and NIE‐115 (adrenergic) neuroblastoma clones after 3 days treatment with dibutyryl cAMP or the phos‐phodiesterase inhibitor N‐4‐(3‐butoxy‐4‐methoxybenzyl)‐2‐imidazolidinone (Ro20‐1724) in an attempt to correlate transcriptional and posttranscriptional changes with observed cAMP‐induced changes in the differentiated state. Treatment of S‐20 cells with dibutyryl cAMP for 3 days caused a fourfold increase in intracellular cAMP and a 30% decrease in growth rate compared with the levels in control cells. However, there was no difference in the synthesis of the poly(A)‐containing RNAs, relative to the ribosomal RNAs, after either 2‐ or 18‐h labeling with 3H‐adenosine. There was also no increase in the steady‐state mRNA levels. Treatment with Ro20‐1724 caused only a transient twofold increase in intracellular cAMP level when S‐20 cells were plated at a low density and no increase at higher densities although growth was inhibited by 60%. There was, again, no increase in the relative synthesis of poly(A)‐mRNAs with 2‐h label in cells treated with Ro20‐1724, but there was a twofold increase after labeling for 18 h. Optical density measurements, however, showed that this increased incorporation of 3H‐adenosine did not result in an increase in the absolute amount of unlabeled poly(A)‐containing mRNAs. NIE‐115 cells showed an 8‐fold increase in intracellular cAMP after 3 days of treatment with Ro20‐1724 and an 80% inhibition of growth rate. However, the relative rates of synthesis of the poly(A)‐containing mRNAs were identical to those obtained using S‐20 cells. These results show that neither increased intracellular cAMP levels nor growth inhibition necessarily result in a relative increase in the synthesis of the poly(A)‐containing mRNAs in these neuroblastoma clones. There was no change in the synthesis or processing of the poly(A) regions of the mRNAs in the S‐20 control and treated cells. In contrast to results with other cells, the poly(A) profiles were heterogeneous, even after 1 hour of labeling. The average size of the poly(A) region decreased similarly in control and drug‐treated cells after 1, 2 and 18 h labeling.