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We examined the pattern of neuroanatomic abnormalities in adults with Down's syndrome (DS) and the cognitive correlates of these abnormalities. Specifically, we compared this pattern with what would be predicted by the hypotheses attributing DS pathology to either premature aging or Alzheimer's disease. We measured a number of brain regions on MRIs of 25 subjects: 13 persons with the DS phenotype and 12 age- and sex-matched healthy volunteers. Study participants had no history of cardiovascular disease, diabetes, thyroid dysfunction, or seizure disorder. After statistical adjustment for differences in body size, we found that, in comparison with controls, DS subjects had substantially smaller cerebral and cerebellar hemispheres, ventral pons, mammillary bodies, and hippocampal formations. In the cerebellar vermis of DS subjects, we observed smaller lobules VI to VIII without appreciable differences in other regions. In addition, we noted trends for shrinkage of the dorsolateral prefrontal cortex, anterior cingulate gyrus, inferior temporal and parietal cortices, parietal white matter, and pericalcarine cortex in DS subjects compared with normal controls. The parahippocampal gyrus was larger in DS subjects. We found no significant group differences in the volumes of the prefrontal white matter, the orbitofrontal cortex, the pre- and postcentral gyri, or the basal ganglia. We conclude that the pattern of selective cerebral damage in DS does not clearly fit the predictions of the premature aging or Alzheimer's disease hypotheses. To examine the relationship between brain abnormalities and cognitive deficits observed in DS, we correlated the size of brain regions that were significantly reduced in DS with performance on tests of intelligence and language. The correlation analysis suggested age-related decline in the DS subjects in general intelligence and basic linguistic skills. General intelligence and mastery of linguistic concepts correlated negatively with the volume of the parahippocampal gyrus. There was no relationship between total brain size and the cognitive variables.
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PMID:Selective neuroanatomic abnormalities in Down's syndrome and their cognitive correlates: evidence from MRI morphometry. 785 39

Sociopolitical and ideological attacks on the various genetically oriented programs of research into the causes of schizophrenia, even when well-motivated to prevent genetic discrimination in all its forms, endangers the enterprise. Although there have been no replicated successes in finding genes linked or associated to markers for schizophrenia yet, the solid foundation for the fact that genetic factors are importantly involved in the etiology of schizophrenia derives from replicated studies using the strategies of genetic epidemiology--families, twins, adoptees. The models to emulate in schizophrenia research should follow the paths of researchers on coronary artery disease, diabetes, and Alzheimer's disease. All are complex diseases with multifactorial and multigenic components. Even when the necessary genotype is present, it may not be expressed as clinical disease at the phenotypic level.
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PMID:Schizophrenia epigenesis: past, present, and future. 787 40

We compared the incidence of risk factors (such as hypertension, diabetes mellitus, hyperlipidemia, hematocrit, atrial fibrillation) and local cerebral blood flow between patients with lacunar infarction associated with leukoaraiosis (LA) in the centrum semiovale (LACS) and those with periventricular white matter lesions (PVWMLs) on magnetic resonance imagings (MRI). Only atrial fibrillation was more frequently seen in LACS (p < 0.05), but the incidence of other risk factors for cerebrovascular disease was not different between the two patient groups. Demented patients were older than those with preserved intelligence in both groups. Local cerebral blood flow was compared between patients with and without dementia by single photon emission computed tomography using N-isopropyl-p-123I iodoamphetamine (IMP). The cerebral: cerebellar IMP uptake ratio (%) was used as a measure of relative cerebral perfusion. Compared with normal controls the demented patients with PVWMLs showed a significant reduction in local cerebral blood flow in the parietal area (p < 0.05) and the basal gray region (p < 0.05), and those with LACS in the frontal area (p < 0.05) and the basal gray region (p < 0.05). A significant positive correlation was found between local cerebral blood flow and dementia rating scales in the temporal and parietal areas in PVWMLs, and in the frontal area in LACS. These results suggest that most patients with LACS may represent vascular dementia of Binswanger type, and some demented patients with PVWMLs may have Alzheimer type dementia.
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PMID:[Cerebral blood flow patterns in patients with leukoaraiosis and lacunar infarction]. 792 55

beta-Amyloid (beta A) is normally produced as a nontoxic soluble peptide. In Alzheimer disease, beta A aggregates and accumulates in the brain as inert diffuse plaques or compact plaques associated with neurodegenerative changes. To determine the relationship of neurotoxicity to the physical state of beta A, we created (i) nonamyloidogenic amorphous aggregates of beta A [amorphous beta A (Am-beta A)] analogous to diffuse plaques and (ii) amyloidogenic fibrils of beta A [fibrillar beta A (Fib-beta A)] analogous to compact plaques. In primary rat hippocampal culture, Fib-beta A was neurotoxic, whereas Am-beta A was not toxic. Fib-beta A caused significant loss of synapses in viable neurons, while Am-beta A had no effect on synapse number. The amyloid fibril-binding dye Congo red inhibited Fib-beta A neurotoxicity by inhibiting fibril formation or by binding to preformed fibrils. Congo red also inhibited the pancreatic islet cell toxicity of diabetes-associated amylin, another type of amyloid fibril. These results indicate that beta A neurotoxicity requires fibril formation. These findings and our previous demonstration that amylin fibrils are toxic suggest that a common cytopathic effect of amyloid fibrils may contribute to the pathogenesis of Alzheimer disease and other amyloidoses.
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PMID:Beta-amyloid neurotoxicity requires fibril formation and is inhibited by congo red. 799 13

This study compares the prevalence rates of 5 common age-dependent diseases in non-demented and demented subjects. Control and dementia populations were approximately age-matched and their numbers also approximated. Prevalence rates for hypertension, myocardial infarction (MI), stroke, cancer and diabetes were determined. The rates of two or more coexisting diseases in the same patient were also compared. Two populations were studied: one was designated the autopsy series, and the other the hospital series. In the autopsy series, the rate of cardiomegaly/hypertension was 1.3 times higher in the control than in the dementia population, and for MI it was 1.7 times higher in the former than in the latter. The rate for stroke was higher in the control group by only a factor of 1.1, for cancer by only a factor of 1.2, and for diabetes the rates were almost identical in the two populations. The rate differences were statistically significant only with respect to cardiomegaly and MI. When the non-vascular and vascular dementias were compared, the rates in the latter were higher by only a factor of 1.3 for cardiomegaly, stroke, cancer and diabetes; for MIs, the rates were about the same in the two dementia categories. The data for two or more coexisting diseases were almost identical in control and dementia autopsy populations. In the hospital series, the hypertension rate was 1.6 times higher in the control than in the Alzheimer's disease (AD) group; for MI, the control group was higher by a factor of 1.5.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Comorbidity of other chronic age-dependent diseases in dementia. 799 23

Human fetal tissue research holds much promise as a therapy for a number of intractable conditions. Likely candidates for fetal tissue therapy include DiGeorge's syndrome, diabetes mellitus, Huntingdon's disease, and Alzheimer's disease. No cure exists for any of these diseases and none, except for fetal tissue therapy, appear on the horizon. Many scientists have thus pushed ahead with research in the field. Since material salvaged from induced abortions primarily serves as the only source for fetal tissue, anti-abortionists are naturally opposed to the research. Proponents of human fetal tissue research, however, argue that the practice is morally separate from abortion and that one's view about the morality of abortion should not affect decisions about the ethics of fetal tissue research and transplant efforts. President Clinton evidently understands this logic, for he lifted the ban on federal funding for such research. The author reviews the impact of human fetal tissue research and transplantation efforts upon the rate of abortion, the concept of informed consent, and the question of complicity to find that abortion and fetal tissue research are indeed morally connected.
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PMID:Abortion and fetal tissue research: some ethical concerns. 806 May 15

Apolipoprotein E (apo E) is a polymorphic glycoprotein that plays an essential part in the binding to receptors for the uptake of chylomicrons and VLDL remnants and of LDL. The three major isoforms are E3 (Cys112/Arg158), E4 (Arg112/Arg158) and E2 (Cys112/Cys158). The apo E genetic variation has a great impact. In most of type III familial hyperlipoproteinemias (HLP), E2 is implicated at the homozygote status. In other cases, rare alleles are directly responsible for dominant type III HLP. Apo E polymorphism is an essential determinant in the interindividual variations of lipids in healthy subjects in various populations. Its influence can be significant on the efficacy of nutritional or therapeutic interventions. The allele epsilon 4 appears to be associated with an increased risk of premature atherosclerosis. Recently, epsilon 4 was demonstrated to be associated with an early Alzheimer's disease onset. Apo E polymorphism contributes to the lipid disorders in diabetes and obesity. The analysis of apo E polymorphism can be carried out with two conceptually different approaches. The first one is based on the separation of plasma isoforms of the protein by isoelectric focusing or bidimensional electrophoresis. The other one consists in the application of molecular biology techniques (PCR and endonuclease restriction profiles) for a detection of the common alleles and of several rare alleles, avoiding the possible errors of the phenotyping technique of the apo E protein. The application of genetic engineering allows a better understanding of the role played by apo E towards its receptors and in other molecular interactions which are not well known up to now.
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PMID:[Pathology of the human apolipoprotein E gene]. 807 81

A variety of degenerative diseases involving deficiencies in mitochondrial bioenergetics have been associated with mitochondrial DNA (mtDNA) mutations. Maternally inherited mtDNA nucleotide substitutions range from neutral polymorphisms to lethal mutations. Neutral polymorphisms are ancient, having accumulated along mtDNA lineages, and thus correlate with ethnic and geographic origin. Mildly deleterious base substitutions have also occurred along mtDNA lineages and have been associated with familial deafness and some cases of Alzheimer's Disease and Parkinson's Disease. Moderately deleterious nucleotide substitutions are more recent and cause maternally-inherited diseases such as Leber's Hereditary Optic Neuropathy (LHON) and Myoclonic Epilepsy and Ragged-Red Fiber Disease (MERRF). Severe nucleotide substitutions are generally new mutations that cause pediatric diseases such as Leigh's Syndrome and dystonia. MtDNA rearrangements also cause a variety of phenotypes. The milder rearrangements generally involve duplications and can cause maternally-inherited adult-onset diabetes and deafness. More severe rearrangements frequently involving detections have been associated with adult-onset Chronic Progressive External Ophthalmoplegia (CPEO) and Kearns-Sayre Syndrome (KSS) or the lethal childhood disorder, Pearson's Marrow/Pancreas Syndrome. Defects in nuclear-cytoplasmic interaction have also been observed, and include an autosomal dominant mutation causing multiple muscle mtDNA deletions and a genetically complex disease resulting in the tissue depletion of mtDNAs. MtDNA nucleotide substitution and rearrangement mutations also accumulate with age in quiescent tissues. These somatic mutations appear to degrade cellular bioenergetic capacity, exacerbate inherited mitochondrial defects and contribute to tissue senescence. Thus, bioenergetic defects resulting from mtDNA mutations may be a common cause of human degenerative disease.
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PMID:Mitochondrial DNA mutations in diseases of energy metabolism. 807 79

In recent years, interest in vascular causes of dementia has increased and it has been proposed that vascular dementia (VAD) may be more common than previously supposed. This may have important implications, because VAD at present may be more amenable to prevention and treatment than Alzheimer's disease (AD). Several vascular factors have been related to cognitive decline and dementia in the elderly, including stroke and white matter disease. However, while numerous case-control studies have been concerned with the risk factors for AD, studies on risk factors for VADs are rare. The problems inherent in the diagnostic criteria make it difficult to interpret the results from the few studies that have been performed. Generally, risk factors for multi-infarct dementia are supposed to be the same as those for stroke, and include hypertension, diabetes mellitus, advanced age, male sex, smoking and cardiac diseases. White matter dementia has mainly been related to hypertension. Recent research suggests that vascular factors may also be important in AD, especially in the late-onset type. In stroke patients, dementia has been associated with higher age, less formal education, cerebral atrophy, left-sided or bilateral infarcts, volume of macroscopic infarcts, bilateral symptoms, previous stroke and white matter lesions. The pathogenetic mechanism through which these factors cause dementia is still not clear. Furthermore, it is not known if risk factors for VAD differ from those found in stroke patients. There is now an urgent need for further research on risk factors for VAD and on factors related to dementia in subjects with cerebrovascular disorders.
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PMID:Risk factors for vascular dementia: a review. 808 68

Primary defects in mitochondrial function are implicated in over 100 diseases, and the list continues to grow. Yet the first mitochondrial defect--a myopathy--was demonstrated only 35 years ago. The field's dramatic expansion reflects growth of knowledge in three areas: (i) characterization of mitochondrial structure and function, (ii) elucidation of the steps involved in mitochondrial biosynthesis, and (iii) discovery of specific mitochondrial DNA. Many mitochondrial diseases are accompanied by mutations in this DNA. Inheritance is by maternal transmission. The metabolic defects encompass the electron transport complexes, intermediates of the tricarboxylic acid cycle, and substrate transport. The clinical manifestations are protean, most often involving skeletal muscle and the central nervous system. In addition to being a primary cause of disease, mitochondrial DNA mutations and impaired oxidation have now been found to occur as secondary phenomena in aging as well as in age-related degenerative diseases such as Parkinson, Alzheimer, and Huntington diseases, amyotrophic lateral sclerosis and cardiomyopathies, atherosclerosis, and diabetes mellitus. Manifestations of both the primary and secondary mitochondrial diseases are thought to result from the production of oxygen free radicals. With increased understanding of the mechanisms underlying the mitochondrial dysfunctions has come the beginnings of therapeutic strategies, based mostly on the administration of antioxidants, replacement of cofactors, and provision of nutrients. At the present accelerating pace of development of what may be called mitochondrial medicine, much more is likely to be achieved within the next few years.
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PMID:The development of mitochondrial medicine. 809 Jul 15


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