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A genome-wide linkage study of insulin-dependent diabetes mellitus (IDDM) using microsatellite markers, obtained from genothon maps and other informative markers derived using polymerase chain reaction analysis, localizes an unidentified susceptibility locus for IDDM. The locus is present in the FGF3 gene area on the chromosome 11Q. Genetic linkage studies also facilitate the identification of susceptibility loci in other multifactorial disorders.

Chromosomal DNA is a complicated affair; in addition to the DNA sequences that specify the amino-acid sequence of protein molecules, there are DNA sequences involved in the regulation of the genes, as well as DNA sequences for which there is no known function. There is a class of alleles (DNA variants which might occur at a particular location on the chromosome) that are associated with insulin-dependent diabetes. These alleles are located on chromosome 11, near the location of the gene for insulin. However, family studies have failed to show that the inheritance of these alleles is associated with the development of diabetes in offspring. Taking a new tack, researchers have found that the inheritance of these genes influences the development of diabetes in some people, but not others. Specific genes of the major histocompatibility complex on chromosome 6 are known to be preferentially associated with many human diseases. When researchers analyzed the inheritance of the alleles on chromosome 11 near the insulin gene, they found that the alleles were an important determinant of insulin-dependent diabetes only for subjects with the gene for the class II histocompatibility molecule HLA-DR4. Subjects who have not inherited the HLA-DR4 gene do not experience an increased risk of diabetes from the gene alleles under question. Curiously, having the HLA-DR4 gene makes no difference if the risky genes are inherited from the mother. Increased risk of diabetes was seen only in individuals who not only had the HLA-DR4 gene, but inherited the risky alleles from their fathers. This observation may provide an explanation for the increased risk of diabetes observed among the children whose fathers have diabetes. It is known that the genetic alleles under study in the present report do not alter the structure of insulin itself. It is suspected, therefore, that these genes change the regulation of the production of insulin. It is also possible, however, that these genes may alter insulin-like growth factor 2 or some other gene that is located in the same general region of the short arm of chromosome 11. (Consumer Summary produced by Reliance Medical Information, Inc.)

Speech perception can be challenging, especially for older adults. Despite the importance of speech perception in social interactions, the mechanisms underlying these difficulties remain unclear and treatment options are scarce. While several studies have suggested that decline within cortical auditory regions may be a hallmark of these difficulties, a growing number of studies have reported decline in regions beyond the auditory processing network, including regions involved in speech processing and executive control, suggesting a potentially diffuse underlying neural disruption, though no consensus exists regarding underlying dysfunctions. To address this issue, we conducted two experiments in which we investigated age differences in speech perception when background noise and talker variability are manipulated, two factors known to be detrimental to speech perception. In Experiment 1, we examined the relationship between speech perception, hearing and auditory attention in 88 healthy participants aged 19 to 87 years. In Experiment 2, we examined cortical thickness and BOLD signal using magnetic resonance imaging (MRI) and related these measures to speech perception performance using a simple mediation approach in 32 participants from Experiment 1. Our results show that, even after accounting for hearing thresholds and two measures of auditory attention, speech perception significantly declined with age. Age-related decline in speech perception in noise was associated with thinner cortex in auditory and speech processing regions (including the superior temporal cortex, ventral premotor cortex and inferior frontal gyrus) as well as in regions involved in executive control (including the dorsal anterior insula, the anterior cingulate cortex and medial frontal cortex). Further, our results show that speech perception performance was associated with reduced brain response in the right superior temporal cortex in older compared to younger adults, and to an increase in response to noise in older adults in the left anterior temporal cortex. Talker variability was not associated with different activation patterns in older compared to younger adults. Together, these results support the notion of a diffuse rather than a focal dysfunction underlying speech perception in noise difficulties in older adults., (Copyright © 2020. Published by Elsevier Inc.)

In this article, we used High Angular Resolution Diffusion Imaging (HARDI) with advanced anatomically constrained particle filtering tractography to investigate the role of the arcuate fasciculus (AF) and the middle longitudinal fasciculus (MdLF) in speech perception in noise in younger and older adults. Fourteen young and 15 elderly adults completed a syllable discrimination task in the presence of broadband masking noise. Mediation analyses revealed few effects of age on white matter (WM) in these fascicles but broad effects of WM on speech perception, independently of age, especially in terms of sensitivity and criterion (response bias), after controlling for individual differences in hearing sensitivity and head size. Indirect (mediated) effects of age on speech perception through WM microstructure were also found, after controlling for individual differences in hearing sensitivity and head size, with AF microstructure related to sensitivity, response bias and phonological priming, and MdLF microstructure more strongly related to response bias. These findings suggest that pathways of the perisylvian region contribute to speech processing abilities, with relatively distinct contributions for the AF (sensitivity) and MdLF (response bias), indicative of a complex contribution of both phonological and cognitive processes to age-related speech perception decline. These results provide new and important insights into the roles of these pathways as well as the factors that may contribute to elderly speech perception deficits. They also highlight the need for a greater focus to be placed on studying the role of WM microstructure to understand cognitive aging., (© 2018 Wiley Periodicals, Inc.)

Healthy aging is associated with a decline in cognitive, executive, and motor processes that are concomitant with changes in brain activation patterns, particularly at high complexity levels. While speech production relies on all these processes, and is known to decline with age, the mechanisms that underlie these changes remain poorly understood, despite the importance of communication on everyday life. In this cross-sectional group study, we investigated age differences in the neuromotor control of speech production by combining behavioral and functional magnetic resonance imaging (fMRI) data. Twenty-seven healthy adults underwent fMRI while performing a speech production task consisting in the articulation of nonwords of different sequential and motor complexity. Results demonstrate strong age differences in movement time (MT), with longer and more variable MT in older adults. The fMRI results revealed extensive age differences in the relationship between BOLD signal and MT, within and outside the sensorimotor system. Moreover, age differences were also found in relation to sequential complexity within the motor and attentional systems, reflecting both compensatory and de-differentiation mechanisms. At very high complexity level (high motor complexity and high sequence complexity), age differences were found in both MT data and BOLD response, which increased in several sensorimotor and executive control areas. Together, these results suggest that aging of motor and executive control mechanisms may contribute to age differences in speech production. These findings highlight the importance of studying functionally relevant behavior such as speech to understand the mechanisms of human brain aging. Hum Brain Mapp 38:2751-2771, 2017. © 2017 Wiley Periodicals, Inc., (© 2017 Wiley Periodicals, Inc.)

The processing of continuous and complex auditory signals such as speech relies on the ability to use statistical cues (e.g. transitional probabilities). In this study, participants heard short auditory sequences composed either of Italian syllables or bird songs and completed a regularity-rating task. Behaviorally, participants were better at differentiating between levels of regularity in the syllable sequences than in the bird song sequences. Inter-individual differences in sensitivity to regularity for speech stimuli were correlated with variations in surface-based cortical thickness (CT). These correlations were found in several cortical areas including regions previously associated with statistical structure processing (e.g. bilateral superior temporal sulcus, left precentral sulcus and inferior frontal gyrus), as well other regions (e.g. left insula, bilateral superior frontal gyrus/sulcus and supramarginal gyrus). In all regions, this correlation was positive suggesting that thicker cortex is related to higher sensitivity to variations in the statistical structure of auditory sequences. Overall, these results suggest that inter-individual differences in CT within a distributed network of cortical regions involved in statistical structure processing, attention and memory is predictive of the ability to detect structural structure in auditory speech sequences.

The processing of fluent speech involves complex computational steps that begin with the segmentation of the continuous flow of speech sounds into syllables and words. One question that naturally arises pertains to the type of syllabic information that speech processes act upon. Here, we used functional magnetic resonance imaging to profile regions, using a combination of whole-brain and exploratory anatomical region-of-interest (ROI) approaches, that were sensitive to syllabic information during speech perception by parametrically manipulating syllabic complexity along two dimensions: (1) individual syllable complexity, and (2) sequence complexity (supra-syllabic). We manipulated the complexity of the syllable by using the simplest syllable template-a consonant and vowel (CV)-and inserting an additional consonant to create a complex onset (CCV). The supra-syllabic complexity was manipulated by creating sequences composed of the same syllable repeated six times (e.g., /pa-pa-pa-pa-pa-pa/) and sequences of three different syllables each repeated twice (e.g., /pa-ta-ka-pa-ta-ka/). This parametrical design allowed us to identify brain regions sensitive to (1) syllabic complexity independent of supra-syllabic complexity, (2) supra-syllabic complexity independent of syllabic complexity and, (3) both syllabic and supra-syllabic complexity. High-resolution scans were acquired for 15 healthy adults. An exploratory anatomical ROI analysis of the supratemporal plane (STP) identified bilateral regions within the anterior two-third of the planum temporale, the primary auditory cortices as well as the anterior two-third of the superior temporal gyrus that showed different patterns of sensitivity to syllabic and supra-syllabic information. These findings demonstrate that during passive listening of syllable sequences, sublexical information is processed automatically, and sensitivity to syllabic and supra-syllabic information is localized almost exclusively within the STP.

Objective: We investigated the natural history of glucokinase (GCK)-related maturity-onset diabetes of the young type 2 (MODY2), notably the factors associated with deterioration of hyperglycemia over time., Research Design and Methods: We report an 11-year follow-up of glucose tolerance and indexes of insulin secretion and insulin sensitivity derived from oral glucose tolerance tests in 33 MODY2 subjects., Results: The variation between tests of glucose tolerance (expressed as the area under the glucose curve) was 6.9 +/- 3.2% (mean +/- SEM), but individual results ranged from -20 to 61%. Deterioration of glucose tolerance between tests was associated with decreased insulin sensitivity, while insulin secretion remained stable., Conclusions: Glucose tolerance can remain stable over many years in subjects with MODY2 due to the relative stability of the GCK-related beta-cell defect. However, the development of insulin resistance may have an important role in the deterioration of the glucose tolerance and in the long-term evolution of the disorder.

Linkage studies have led to the identification of several chromosome regions that may contain susceptibility loci to type I diabetes (IDDM), in addition to the HLA and INS loci. These include two on chromosome 6q, denoted IDDM5 and IDDM8, that are not linked to HLA. In a previous study, we noticed that the evidence for linkage to IDDM susceptibility around the HLA locus extended over a total distance of 100 cM, which suggested to us that another susceptibility locus could reside near HLA. We developed a statistical method to test this hypothesis in a panel of 523 multiplex families from France, the United States, and Denmark (a total of 667 affected sib pairs, 536 with both parents genotyped), and here present evidence (P = .00003) of a susceptibility locus for IDDM located 32 cM from HLA in males but not linked to HLA in females and distinct from IDDM5 and IDDM8. A new statistical method to test for the presence of a second susceptibility locus linked to a known first susceptibility locus (here HLA) is presented. In addition, we analyzed our current family panel with markers for IDDM5 and IDDM8 on chromosome 6 and found suggestions of linkage for both of these loci (P = .002 and .004, respectively, on the complete family panel). When cumulated with previously published results, with overlapping families removed, the affected-sib-pair tests had a significance of P = .0001 for IDDM5 and P = .00004 for IDDM8.

Although existence of islet cell antibodies (ICA) is regarded as secondary to beta cell death, islet cell surface antibodies (ICSA) might play a role in the disease process. We have collected information from nine European clinics to determine whether ICSA are more common in diabetic children or their relatives in geographical areas or time periods of high incidence of insulin-dependent diabetes mellitus (IDDM). In Finland and Sweden ("North group") with a high incidence of IDDM during childhood, 36% of the patients were positive or weakly positive for ICSA at diagnosis compared with 24% in France (p = 0.1), 11% in Berlin-Vienna (p < 0.01), and 14% in Italy (p < 0.01). This difference was seen in all age groups but was most pronounced in the youngest (0-4 y). This geographical difference was also seen among family members of whom 46% were positive or weakly positive in the North group, 25% in France (p < 0.001), 21% in Berlin-Vienna (p < 0.001), and 16% in Italy (p < 0.001). Of several analyzed antibodies (ICA, gastric parietal cell, thyroglobulin, and thyroid microsomal), only ICSA showed simultaneous positivity in all family members (r = 0.32, p < 0.01). ICSA were most common in family members of patients with short (< 8 d) duration of symptoms (p < 0.05) and showed a similar seasonality, both in patients and relatives, as the incidence of IDDM. We conclude that the geographical difference in incidence of childhood IDDM in Europe may be associated to similar geographical differences in occurrence of ICSA both in newly diagnosed diabetic children and in their relatives. Simultaneous existence of ICSA in both patients and family members and a similar seasonality for ICSA and incidence of IDDM suggest that ICSA may reflect an ongoing disease process.

Among patients with insulin-dependent diabetes mellitus (IDDM), an excess of DR3 and DR4 alleles is classically described when compared with the general population. In addition, an excess of maternal DR3 and paternal DR4 alleles among patients (DR3DR4) is observed. In order to explain these observations, two alternative hypotheses can be tested: maternal effect and parental imprinting. Maternal effect has been tested and not rejected on a sample of 416 caucasians affected with IDDM. Under this hypothesis, the children of a DR3 mother are expected to have an earlier exposure and, hence, an earlier age at onset. However, we did not observe such a difference in age at onset in this data set. Using the marker-association-segregation-chi 2 method, we have tested four hypotheses with different parental effects of two susceptibility alleles, alpha 0 and beta 0, at two different closely linked loci. Under the hypothesis that best fitted the data, the probability of being affected depended on the parental inheritance of the susceptibility alleles, suggesting parental imprinting (i.e., differential role of maternal and paternal allele), without evidence for a cis-trans effect. We conclude that parental imprinting on a specific allelic combination may explain the observations on the HLA genotypes of the patients and their relatives.

The marker association segregation chi-square (MASC) method was applied to a sample of 416 Caucasians affected with insulin-dependent diabetes mellitus (IDDM), for which information on the parental and sibship status was available, as well as HLA typing. We show that the model which best explains all the observations assumes a cis or trans complementation of two tightly linked genes within the HLA region, an additional maternal effect, and other familial factors. The HLA molecule corresponding to the complementation of Arg52(+) and Asp57(-) has been recently proposed as explaining susceptibility to IDDM. However, this hypothesis does not account for the overall observations made on the HLA marker in IDDM patients and their relatives. The MASC method may also be applied to evaluate the risk for relatives of an affected individual (the "index"). For example, the risk for a sib depends not only on the parental status and on the number of HLA haplotypes he shares with the index, but also on which haplotype the index himself inherited from his mother and father.

Insulin-dependent diabetes mellitus (IDDM) has a complex pattern of genetic inheritance. In addition to genes mapping to the major histocompatibility complex (MHC), several lines of evidence point to the existence of other genetic susceptibility factors. Recent studies of the nonobese diabetic mouse (NOD) model of IDDM have suggested the presence, on mouse chromosome 9, of a susceptibility gene linked to the locus encoding the T-cell antigen, Thy-1. A region on human chromosome 11q is syntenic to this region on mouse chromosome 9. We have used a set of polymorphic DNA markers from chromosome 11q to investigate this region for linkage to a susceptibility gene in 81 multiplex diabetic pedigrees. The data were investigated by maximization of lod scores over genetic models and by multiple-locus affected-sib-pair analysis. We were able to exclude the presence of a susceptibility gene (location scores less than -2) throughout greater than 90% of the chromosome 11q homology region, under the assumption that the susceptibility factor would cause greater than 50% of affected sib pairs to share two alleles identical by descent. Theoretical estimates of the power to map susceptibility genes with a high-resolution map of linked markers in a candidate region were made, using HLA as a model locus. This result illustrates the feasibility that IDDM linkage studies using mapped sets of polymorphic DNA markers have, both for other areas of the genome in IDDM and for other polygenic diseases. The analytic approaches introduced here will be useful for affected-sib-pair studies of other complex phenotypes.

The lod score method has been applied to 28 informative families with at least one child suffering from juvenile insulin-dependent diabetes (JIDD), assuming autosomal recessive inheritance, for detection of linkage between HLA and a susceptibility locus for this disease. These 28 families were pooled with 21 other families from the literature. The maximum lod scores were obtained for recombination fractions from 4 to 16%, according to the level of penetrance (10 to 90%). These high estimates of the recombination fraction are not in agreement with the hypothesis that the association between JIDD and specific HLA haplotypes is due to a simple linkage disequilibrium between the HLA region and a susceptibility locus for JIDD.