Auto-Contractive Maps: an artificial adaptive system for data mining. An application to Alzheimer disease.

This article presents a new paradigm of Artificial Neural Networks (ANNs): the Auto-Contractive Maps (Auto-CM). The Auto-CM differ from the traditional ANNs under many viewpoints: the Auto-CM start their learning task without a random initialization of their weights, they meet their convergence criterion when all their output nodes become null, their weights matrix develops a data driven warping of the original Euclidean space, they show suitable topological properties, etc. Further two new algorithms, theoretically linked to Auto-CM are presented: the first one is useful to evaluate the complexity and the topological information of any kind of connected graph: the H Function is the index to measure the global hubness of the graph generated by the Auto-CM weights matrix. The second one is named Maximally Regular Graph (MRG) and it is an development of the traditionally Minimum Spanning Tree (MST). Finally, Auto-CM and MRG, with the support of the H Function, are applied to a real complex dataset about Alzheimer disease: this data come from the very known Nuns Study, where variables measuring the abilities of normal and Alzheimer subject during their lifespan and variables measuring the number of the plaques and of the tangles in their brain after their death. The example of the Alzheimer data base is extremely useful to figure out how this new approach can help to re design bottom-up the overall structure of factors related to a complex disease like this.

Delayed recall, hippocampal volume and Alzheimer neuropathology: findings from the Nun Study.

OBJECTIVE: To examine the associations of hippocampal volume and the severity of neurofibrillary lesions determined at autopsy with delayed verbal recall performance evaluated an average of 1 year prior to death. METHODS: Hippocampal volumes were computed using postmortem brain MRI from the first 56 scanned participants of the Nun Study. Quantitative neuropathologic studies included lesion counts, Braak staging, and determination of whether neuropathologic criteria for Alzheimer disease (AD) were met. Multiple regression was used to assess the association of hippocampal volume and neuropathologic lesions with the number of words (out of 10) recalled on the Consortium to Establish a Registry for Alzheimer's Disease Delayed Word Recall Test administered an average of 1 year prior to death. RESULTS: When entered separately, hippocampal volume, Braak stage, and the mean neurofibrillary tangle counts in the CA-1 region of the hippocampus and the subiculum were strongly associated with the number of words recalled after a delay, adjusting for age and education. When hippocampal volume was entered together with each neuropathologic index, only hippocampal volume retained a significant association with the delayed recall measure. The association between hippocampal volume and the number of words recalled was present in both demented and nondemented individuals as well as in those with and without substantial AD neurofibrillary pathology. CONCLUSIONS: The association of neurofibrillary tangles with delayed verbal recall may reflect associated hippocampal atrophy.

Hippocampal volume as an index of Alzheimer neuropathology: findings from the Nun Study.

OBJECTIVE: To determine whether hippocampal volume is a sensitive and specific indicator of Alzheimer neuropathology, regardless of the presence or absence of cognitive and memory impairment. METHODS: Postmortem MRI scans were obtained for the first 56 participants of the Nun Study who were scanned. The area under receiver operating characteristic curves, sensitivity, specificity, and positive and negative predictive values were used to assess the diagnostic accuracy of hippocampal volume in predicting fulfillment of Alzheimer neuropathologic criteria and differences in Braak staging. RESULTS: Hippocampal volume predicted fulfillment of neuropathologic criteria for AD for all 56 participants (p < 0.001): 24 sisters who were demented (p = 0.036); 32 sisters who remained nondemented (p < 0.001), 8 sisters who remained nondemented but had memory impairment (p < 0.001), and 24 sisters who were intact with regard to memory and cognition at the final examination prior to death (p = 0.003). In individuals who remained nondemented, hippocampal volume was a better indicator of AD neuropathology than a delayed memory measure. Among nondemented sisters, Braak stages III and VI were distinguishable from Braak stages II or lower (p = 0.001). Among cognitively intact individuals, those in Braak stage II could be distinguished from those in stage I or less (p = 0.025). CONCLUSION: Volumetric measures of the hippocampus may be useful in identifying nondemented individuals who satisfy neuropathologic criteria for AD as well as pathologic stages of AD that may be present decades before initial clinical expression.

An automated technique for measuring hippocampal volumes from MR imaging studies.

We describe an automated volumetric measure of the hippocampus obtained with software called the Knowledge-Guided MRI Analysis Program (KGMAP). Postmortem MR images from 56 participants in the Nun Study were used to validate the measure. KGMAP-determined volumes strongly correlated with those obtained with manual tracings and neurofibrillary pathologic findings of Alzheimer disease in the hippocampus. KGMAP provides a rapid and accurate estimate of hippocampal volume that is suitable for use in clinical practice.

Positive emotions in early life and longevity: findings from the nun study.

Handwritten autobiographies from 180 Catholic nuns, composed when participants were a mean age of 22 years, were scored for emotional content and related to survival during ages 75 to 95. A strong inverse association was found between positive emotional content in these writings and risk of mortality in late life (p < .001). As the quartile ranking of positive emotion in early life increased, there was a stepwise decrease in risk of mortality resulting in a 2.5-fold difference between the lowest and highest quartiles. Positive emotional content in early-life autobiographies was strongly associated with longevity 6 decades later. Underlying mechanisms of balanced emotional states are discussed.

Cognitive function and apolipoprotein E in very old adults: findings from the Nun Study.

OBJECTIVES: The epsilon4 allele of apolipoprotein E (APOE) has been associated with Alzheimer' s disease and with milder forms of cognitive impairment. We investigated the possibility that the absence of the epsilon4 allele may predict the maintenance of high cognitive function among very old individuals. METHODS: Our data are from the Nun Study, a longitudinal study of aging and Alzheimer's disease in 678 Catholic sisters. All sisters participate in annual functional exams that include the Consortium to Establish a Registry for Alzheimer's Disease (CERAD) battery of cognitive tests. High cognitive function was defined as intact scores on five of the CERAD tests. A total of 241 participants aged 75 to 98 met this criterion at the first exam. RESULTS: Findings showed that 62% of the 241 participants maintained intact scores on the five CERAD tests throughout their participation in the study. Life table analyses indicated that those without the APOE epsilon4 allele spent more time with intact cognitive function than those with the epsilon4 allele (p = .007). Cox regression analyses indicated that those without the epsilon4 allele had half the risk of losing their intact status during the study when compared with those with the epsilon4 allele (p < .01). DISCUSSION: Our findings suggest that the APOE epsilon4 allele may be included among the variables that predict high cognitive function in cognitively intact, very old adults. Although the presence or absence of the epsilon4 allele is known to be related to the risk of dementia, it also appears to be related to maintaining high levels of cognitive function in old age.

Linguistic ability in early life and the neuropathology of Alzheimer's disease and cerebrovascular disease. Findings from the Nun Study.

Findings from the Nun Study indicate that low linguistic ability in early life has a strong association with dementia and premature death in late life. In the present study, we investigated the relationship of linguistic ability in early life to the neuropathology of Alzheimer's disease and cerebrovascular disease. The analyses were done on a subset of 74 participants in the Nun Study for whom we had handwritten autobiographies completed some time between the ages of 19 and 37 (mean = 23 years). An average of 62 years after writing the autobiographies, when the participants were 78 to 97 years old, they died and their brains were removed for our neuropathologic studies. Linguistic ability in early life was measured by the idea (proposition) density of the autobiographies, i.e., a standard measure of the content of ideas in text samples. Idea density scores from early life had strong inverse correlations with the severity of Alzheimer's disease pathology in the neocortex: Correlations between idea density scores and neurofibrillary tangle counts were -0.59 for the frontal lobe, -0.48 for the temporal lobe, and -0.49 for the parietal lobe (all p values < 0.0001). Idea density scores were unrelated to the severity of atherosclerosis of the major arteries at the base of the brain and to the presence of lacunar and large brain infarcts. Low linguistic ability in early life may reflect suboptimal neurological and cognitive development, which might increase susceptibility to the development of Alzheimer's disease pathology in late life.

Serum folate and the severity of atrophy of the neocortex in Alzheimer disease: findings from the Nun study.

BACKGROUND: Previous studies suggested that low concentrations of folate in the blood are related to poor cognitive function, dementia, and Alzheimer disease-related neurodegeneration of the brain. OBJECTIVE: Our aim was to determine whether serum folate is inversely associated with the severity of atrophy of the neocortex. DESIGN: Nutrients, lipoproteins, and nutritional markers were measured in the blood of 30 participants in the Nun Study from one convent who later died when they were 78-101 y old (mean: 91 y). At autopsy, several neuropathologic indicators of Alzheimer disease were determined, including the degree of atrophy of 3 lobes of the neocortex (frontal, temporal, and parietal) and the number of neocortical Alzheimer disease lesions (ie, senile plaques and neurofibrillary tangles) as assessed by a neuropathologist. RESULTS: The correlation between serum folate and the severity of atrophy of the neocortex was -0.40 (P = 0.03). Among a subset of 15 participants with significant numbers of Alzheimer disease lesions in the neocortex, the correlation between folate and atrophy was -0.80 (P = 0.0006). Atrophy may be specific to low folate because none of the 18 other nutrients, lipoproteins, or nutritional markers measured in the blood had significant negative correlations with atrophy. CONCLUSIONS: Among elderly Catholic sisters who lived in one convent, ate from the same kitchen, and were highly comparable for a wide range of environmental and lifestyle factors, low serum folate was strongly associated with atrophy of the cerebral cortex. Definitive evidence for this relation and its temporal sequence awaits the findings of other studies.

White matter volumes and periventricular white matter hyperintensities in aging and dementia.

OBJECTIVE: To determine the relationship between MRI periventricular white matter hyperintensities, cerebral white matter volumes, neuropathologic findings, and cognitive status in aged individuals. BACKGROUND: The significance of periventricular white matter hyperintensities seen on MR images in aged individuals remains controversial. The Nun Study is a longitudinal cohort aging study in which all 678 initially enrolled participants agreed to autopsy neuropathologic examination. METHODS: We used MRI to measure white matter volumes of the cerebral hemispheres in 52 formaldehyde-fixed brains for correlation with white matter and neocortical pathology, postmortem MRI observations, and cognitive measures. RESULTS: Reduced white matter volume is associated with dementia, but periventricular white matter hyperintensities were not related to white matter volume, stroke, or dementia. CONCLUSIONS: Our results do not support the hypothesis that periventricular hyperintensities seen on MR images have deleterious consequences in these aged individuals.

Periventricular white matter hyperintensities on MRI: correlation with neuropathologic findings.

Periventricular white matter hyperintensities on postmortem magnetic resonance imaging (MRI) and myelin-stained frontal and parietal histologic sections were evaluated independently in 12 cases. There was a strong relationship between the extent of white matter hyperintensities on MRI and the extent of gross and microscopic changes seen in the white matter of myelin-stained sections, particularly in the frontal lobe. In this material, the extent of myelin rarefaction correlated with a 0- to 8-point white matter hyperintensity scale rating on MRI in the same brains.

Progression of regional neuropathology in Alzheimer disease and normal elderly: findings from the Nun study.

Although diffuse plaques in the neocortex may represent an early stage in the evolution of neuritic plaques, plaques in the striatum and cerebellum retain their predominantly diffuse nature in Alzheimer disease (AD), regardless of disease duration. We had the opportunity to explore the progression of these regional features by using autopsy brain specimens from 15 cognitively normal and five AD subjects, all Catholic sisters enrolled in the Nun Study, a longitudinal study on aging and AD. Neuropathologic changes were assessed in the temporal cortex, striatum, and cerebellum without knowledge of clinical status. We found diffuse plaques in the striatum in six (40%) and cerebellar plaques in none of the brains from the non-demented subjects. Striatal plaques were present in all five and cerebellar plaques in four of the five AD cases. In the 20 cases overall, the presence of striatal plaques generally paralleled the occurrence of neuritic plaques in neocortex and correlated with lower scores on several neuropsychologic tests assessing memory. Our findings suggest that striatal diffuse plaques occur relatively early in the progression of AD pathology and coincide with neocortical pathology and cognitive changes. Thus, it is unlikely that temporal factors alone account for regional differences in progression of AD neuropathology.

Alzheimer's disease, dental amalgam and mercury.

BACKGROUND: Mercury, or Hg, is a neurotoxin that has been speculated to play a role in the pathogenesis of Alzheimer's disease, or AD. Dental amalgam releases low levels of Hg vapor and is a potential source of Hg for a large segment of the adult population. METHODS: The authors studied 68 subjects with AD and 33 control subjects without AD to determine Hg levels in multiple brain regions at autopsy and to ascertain the subjects' dental amalgam status and history. The subjects were from central Kentucky and Elm Grove, Wis. The authors conducted dental amalgam assessments during the lives of the majority of subjects and in some subjects at the time of autopsy only. The authors also determined three dental amalgam index scores--Event (placement, repair or removal of amalgam), Location and Time In Mouth--in addition to the numbers of and surface area of occlusal amalgam restorations. The authors determined Hg levels in multiple brain regions and performed full neuropathologic evaluations to confirm the normal status of the brain or the presence of AD. RESULTS: The authors found no significant association of AD with the number, surface area or history of having dental amalgam restorations. They also found no statistically significant differences in brain Hg level between subjects with AD and control subjects. CONCLUSIONS: Hg in dental amalgam restorations does not appear to be a neurotoxic factor in the pathogenesis of AD. The authors found that brain Hg levels are not associated with dental amalgam, either from existing amalgam restorations or according to subjects' dental amalgam restoration history. CLINICAL IMPLICATIONS: Dental amalgam restorations, regardless of number, occlusal surface area or time, do not relate to brain Hg levels.

Self-rated function, self-rated health, and postmortem evidence of brain infarcts: findings from the Nun Study.

OBJECTIVES: Self-rated function is a new global measure. Previous findings suggest that self-rated function predicts future functional decline and is strongly associated with all-cause mortality. We hypothesized that the strength of the relationship of self-rated function to all-cause mortality was in part due to functional decline, such as would occur with brain infarcts. METHODS: Self-ratings of function and health (on a 5-point scale, ranging from excellent to poor) were assessed annually on 630 participants in the Nun Study. Mortality surveillance extended from October 31, 1991 to March 1, 1998, and, among those who died, neuropathological examination determined postmortem evidence of brain infarcts. Cox regression modeling with self-rated function and health as time-dependent covariates and stratification by assessment period were used in these analyses. RESULTS: Self-rated function and health ratings of good, fair, and poor were significantly associated with doubling of the risk of mortality, compared with ratings of very good and excellent. Self-rated function ratings of fair or poor were associated with a threefold increase in the risk of mortality with brain infarcts, but self-rated function and health ratings of fair and poor were comparable in their association with all-cause mortality and mortality without brain infarcts. DISCUSSION: Self-rated function was significantly associated with mortality with brain infarcts, suggesting that brain infarcts may be experienced as functional loss but not recognized or labeled as disease. Our results suggest that self-rated function and health should be explored simultaneously in future research.

Immunocytochemical localization of inducible nitric oxide synthase and transforming growth factor-beta (TGF-beta) in leprosy lesions.

Inducible nitric oxide synthase (iNOS) and TGF-beta were localized by immunocytochemistry in skin lesions from patients across the leprosy spectrum, and from patients undergoing reversal reaction. iNOS expression was highest at the tuberculoid pole of the spectrum, and increased during reversal reaction. TGF-beta was observed throughout the leprosy spectrum, but was highest at the lepromatous pole. Levels of TGF-beta decreased during reversal reaction. Reduced levels of TGF-beta may contribute to unregulated inflammatory responses during reactional episodes.

Height as a marker of childhood development and late-life cognitive function: the Honolulu-Asia Aging Study.

OBJECTIVE: Growing evidence suggests that structural and functional brain reserves, thought to develop in childhood and adolescence, may be crucial in determining when cognitive impairment begins. The purpose of this report is to examine the relationship of height, as a marker of childhood development, to late-life cognitive function in a sample of elderly Japanese-American men. METHOD: Cognitive performance was assessed from 1991 to 1993 in the Honolulu-Asia Aging Study in 3733 men aged 71 to 93 years and related to height that was measured 25 years earlier. RESULTS: Among the study sample, shorter men were older, leaner, and less educated than taller men. Shorter men also spent more years of their childhood living in Japan and were more likely to have had fathers in unskilled professions. After adjustment for age, the prevalence of poor cognitive performance declined consistently with increasing height from 25% in men shorter than 154 cm (61 in) to 9% in those taller than 174 cm (69 in). Excluding men with stroke or dementia did not alter the association between height and cognitive performance. Apolipoprotein E4 was unrelated to height and did not effect the association between height and cognitive function. The prevalence of Alzheimer's disease was higher in men who were 154 cm (61 in) or shorter as compared with men who were taller (4.7% vs 2.9%, respectively). There was no association between height and vascular dementia. CONCLUSION: Efforts to improve prenatal and early life conditions to maximize growth in childhood and adolescence could diminish or delay the expression of cognitive impairments that occur later in life. Prevention of some late-life cognitive impairments may have pediatric origins.

Activity of disulfiram (bis(diethylthiocarbamoyl)disulphide) and ditiocarb (diethyldithiocarbamate) against metronidazole-sensitive and -resistant Trichomonas vaginalis and Tritrichomonas foetus.

Clinical resistance of Trichomonas vaginalis to metronidazole is best correlated with MIC values measured under aerobic conditions. Under these conditions both disulfiram (bis(diethylthiocarbamoyl)disulphide), and its first mammalian metabolite, ditiocarb (diethyldithiocarbamate), showed high levels of activity against metronidazole-sensitive (disulfiram MIC, 0.1-0.7 microM; ditiocarb MIC, 0.3-9 microM) and -resistant (MICs 0.2-1.3 microM and 1.2-9 microM respectively) isolates. Tritrichomonas foetus was also sensitive-the MICs for seven metronidazole-sensitive isolates were 0.1-1.0 microM for disulfiram and 1.0-6.9 microM for ditiocarb; those for two highly metronidazole-resistant strains were 0.3-1.3 microM and 0.6-6 microM respectively. Under anerobic conditions most strains became highly resistant to both compounds. Surprisingly, disulfiram was consistently more active than ditiocarb.

Structure-activity relationships for the antileishmanial and antitrypanosomal activities of 1'-substituted 9-anilinoacridines.

Members of the class of 9-anilinoacridine topoisomerase II inhibitors bearing lipophilic electron-donating 1'-anilino substituents are active against both the promastigote and amastigote forms of the parasite Leishmania major. A series of analogues of the known 1'-NHhexyl lead compound were prepared and evaluated against L. major in macrophage culture to further develop structure-activity relationships (SAR). Toxicity toward mammalian cells was measured in a human leukemia cell line, and the ratio of the two IC50 values (IC50(J)/IC50(L)) was used as a measure of the in vitro therapeutic index (IVTI). A 3,6-diNMe2 substitution pattern on the acridine greatly increased toxicity to L. major without altering mammalian toxicity, increasing IVTIs over that of the lead compound. The 2-OMe, 6-Cl acridine substitution pattern used in the antimalarial drug mepacrine also resulted in potent antileishmanial activity and high IVTIs. Earlier suggestions of the utility of 2'-OR groups in lowering mammalian cytotoxicity were not borne out in this wider study. A series of very lipophilic 1'-NRR (symmetric dialkylamino)-substituted analogues showed relatively high antileishmanial potency, but no clear trend was apparent across the series, and none were superior to the 1'-NH(CH2)5Me subclass. Subsets of the most active 1'-N(R)(CH2)5Me- and 1'-N(alkyl)2-substituted compounds against L. major were also evaluated against Leishmania donovani, Trypanosoma cruzi, and Trypanosoma brucei, but no consistent SAR could be discerned in these physiologically diverse test systems. The present study has confirmed earlier conclusions that lipophilic electron-donating groups at the 1'-position of 9-anilinoacridines provide high activity against L. major, but the SAR patterns observed do not carry over to the other parasites studied.