Biomedical subjects

Tatiana M Foroud

Publications and source records attributed to Tatiana M Foroud.

11 recordsLinked to original sources

PubMed2025

Comprehensive cross-sectional and longitudinal comparisons of plasma glial fibrillary acidic protein and neurofilament light across FTD spectrum disorders.

BACKGROUND: Therapeutic development for frontotemporal dementia (FTD) is hindered by the lack of biomarkers that inform susceptibility/risk, prognosis, and the underlying causative pathology. Blood glial fibrillary acidic protein (GFAP) has garnered attention as a FTD biomarker. However, investigations of GFAP in FTD have been hampered by symptomatic and histopathologic heterogeneity and small cohort sizes contributing to inconsistent findings. Therefore, we evaluated plasma GFAP as a FTD biomarker and compared its performance to that of neurofilament light (NfL) protein, a leading FTD biomarker. METHODS: We availed ARTFL LEFFTDS Longitudinal Frontotemporal Lobar Degeneration (ALLFTD) study resources to conduct a comprehensive cross-sectional and longitudinal examination of the susceptibility/risk, prognostic, and predictive performance of GFAP and NfL in the largest series of well-characterized presymptomatic FTD mutation carriers and participants with sporadic or familial FTD syndromes. Utilizing single molecule array technology, we measured GFAP and NfL in plasma from 161 controls, 127 presymptomatic mutation carriers, 702 participants with a FTD syndrome, and 67 participants with mild behavioral and/or cognitive changes. We used multivariable linear regression and Cox proportional hazard models adjusted for co-variates to examine the biomarker utility of baseline GFAP and NfL concentrations or their rates of change. RESULTS: Compared to controls, GFAP and NfL were elevated in each FTD syndrome but GFAP, unlike NfL, poorly discriminated controls from participants with mild symptoms. Similarly, both baseline GFAP and NfL were higher in presymptomatic mutation carriers who later phenoconverted, but NfL better distinguished non-converters from phenoconverters. We additionally observed that GFAP and NfL were associated with disease severity indicators and survival, but NfL far outperformed GFAP. Nevertheless, we validated findings that the GFAP/NfL ratio may discriminate frontotemporal lobar degeneration with tau versus TDP-43 pathology. CONCLUSIONS: Our head-to-head comparison of plasma GFAP and NfL as biomarkers for FTD indicate that NfL consistently outmatched GFAP as a prognostic and predictive biomarker for participants with a FTD syndrome, and as a susceptibility/risk biomarker for people at genetic risk of FTD. Our findings underscore the need to include leading biomarkers in investigations evaluating new biomarkers if the field is to fully ascertain their performance and clinical value.

Humans↗

PubMed2025

The Consortium for Clarity in ADRD Research Through Imaging (CLARiTI): Overview of consortium sites and anticipated enrollment.

INTRODUCTION: The Consortium for Clarity in Alzheimer's disease related dementias (ADRD) Research Through Imaging (CLARiTI) is a study that aims to collect standardized imaging and plasma biomarkers on 2000 Clinical Core participants enrolled across all Alzheimer's Disease Research Centers (ADRC) sites. We sought to summarize the known heterogeneity across centers regarding scientific focus and initial enrollment plans for CLARiTI. METHODS: We developed and distributed a survey capturing information on the 36 CLARiTI site's theme/expertise, recruitment plans, and the intersection of CLARiTI with other ADRC imaging efforts. RESULTS: Anticipated CLARiTI enrollees spanned 11 different categories of suspected etiologies underlying impairment. A wide range of risk factors were endorsed across sites regarding the enrollment of unimpaired individuals. Variability also existed regarding site-level strategies in enrollment into CLARiTI versus other imaging efforts. DISCUSSION: We anticipate that the 2000 individuals that will enroll into CLARiTI will reflect the clinical heterogeneity already in place across the ADRC network. HIGHLIGHTS: The ADRC Consortium for Clarity in ADRD Research Through Imaging (CLARiTI) will leverage and contribute to the existing Alzheimer's Disease Research Centers (ADRC) program by supporting standardized imaging and plasma collection across all centers. We summarize the variation in scientific focus and enrollment plans across ADRC sites participating in CLARiTI. The anticipated CLARiTI cohort will reflect the clinical heterogeneity that already exists across the ADRC network. CLARiTI will contribute to scientific goals related to the detection of multi-etiological signatures relevant for Alzheimer's disease and related disorders (ADRDs).

Humans↗

PubMed2006

Human ALOX12, but not ALOX15, is associated with BMD in white men and women.

UNLABELLED: The Alox15 gene was recently identified as a negative regulator of peak BMD in mice. Polymorphisms in human ALOX12, but not ALOX15, were significantly associated with spine BMD in white men and women, suggesting that ALOX12 may contribute to normal variation in BMD. INTRODUCTION: Osteoporosis is a complex disease with both genetic and environmental risk factors. A major determinant of osteoporosis is peak BMD, which is a highly heritable trait. Recently, the arachidonate 15-lipoxygenase (Alox15) gene was identified as a negative regulator of peak BMD in mice. MATERIALS AND METHODS: To assess the contribution of lipoxygenase genes to normal BMD variation in healthy white men and women, we performed population- and family-based association studies of two arachidonate lipoxygenase genes: ALOX15, which is the human homolog of mouse Alox15, and ALOX12, which is functionally similar to Alox15. Single nucleotide polymorphisms (SNPs) distributed across the two genes were genotyped. BMD was measured at the femoral neck and lumbar spine in 411 men 18-61 years of age and 1291 premenopausal women 20-50 years of age. RESULTS: Moderate evidence of association was found between spine BMD and six SNPs in the ALOX12 gene in both men and women (p = 0.0052-0.050). Furthermore, the most common SNP haplotype in ALOX12 showed evidence of significant association with high spine BMD in men (p = 0.0083), whereas the second most common haplotype was associated with high spine BMD in women (p = 0.0081). CONCLUSIONS: Polymorphisms in the ALOX12 gene may contribute to normal variation in spine BMD.

Adolescent↗

PubMed2006

Clinical features of Parkinson disease patients with homozygous leucine-rich repeat kinase 2 G2019S mutations.

BACKGROUND: The G2019S mutation is the most common pathogenic substitution in the leucine-rich repeat kinase 2 (LRRK2) gene, which has recently been identified in familial and sporadic Parkinson disease (PD). OBJECTIVES: To report the clinical characteristics of PD patients with homozygous LRRK2 6055G>A (G2019S) mutations and to compare them with previously published descriptions of heterozygous patients. DESIGN: Descriptive clinical report from an international consortium of studies. Subjects Patients with familial PD and homozygous LRRK2 mutations included 23 Tunisians, 2 Algerians, 2 US patients, 1 Canadian, and 1 Moroccan. RESULTS: There were no observable differences between the homozygote and heterozygote phenotypes. CONCLUSIONS: Parkinson disease related to LRRK2 is characterized by typical clinical features, and the similarities between patients with homozygous and heterozygous mutations do not support a gene dosage effect.

Aged↗

PubMed2006

Heritability of changes in bone size and bone mass with age in premenopausal white sisters.

UNLABELLED: Femoral neck area expands and BMD decreases in premenopausal women. We used longitudinal DXA measurements on 388 premenopausal white sisters to show significant heritability of the rates of change in femoral neck area, BMC, and BMD. INTRODUCTION: Bone mass and structure are highly heritable. However, genetic effects on age-related changes in bone mass and structure in adults have been much less studied. MATERIALS AND METHODS: DXA measurements were made on 388 healthy white premenopausal sisters from 178 families. Rates of change in femoral neck area, BMC, and BMD, as well as body weight, were calculated from two measurements made an average of 5.7 years apart. Mixed models were used to test whether bone changes were related to age or weight change. Variance components models were used to estimate the heritability of the rates of change. A method was proposed to correct for the underestimation of heritabilities caused by measurement errors of the rates of change. RESULTS: Femoral neck area increased with age, whereas BMD decreased. All of the rates of change at the femoral neck were positively correlated with weight change, but the rates of femoral neck changes did not vary with age. Adjusted for weight change, change in femoral neck BMC became negative. Significant heritabilities (0.29-0.36) were detected for changes in femoral neck BMC, BMD, and area adjusted for weight changes. Correction for DXA measurement error in the rate estimates increased the heritability estimates (from 0.29-0.36 range to 0.37-0.64 range). CONCLUSIONS: Rates of change are heritable for femoral neck area, BMC, and BMD in premenopausal white women.

Adult↗

PubMed2005

Root resorption associated with orthodontic force in inbred mice: genetic contributions.

Root resorption (RR) is an unwanted sequela of orthodontic treatment. Despite rigorous investigation, no single factor or group of factors that directly causes RR has been identified. The purpose of this study was to examine the effect of the genotype on susceptibility or resistance to develop RR secondary to orthodontic force. Nine-week-old male mice from eight inbred strains were used and randomly distributed into control (C) or treatment (T) groups as follows: A/J (C = 9,T = 9), C57BL/6J (C = 7,T = 8), C3H/HeJ (C = 8,T = 6), BALB/cJ (C = 8,T = 6), 129P3/J (C = 6,T = 8), DBA/2J (C = 8,T = 9), SJL/J (C = 8,T = 10), and AKR/J (C = 9,T = 8). Each of the treated mice received an orthodontic appliance to tip the maxillary left first molar mesially for 9 days. Histological sections of the tooth were used to determine RR and tartrate resistant acid phosphatase (TRAP) activity. The Wilcoxon ranked-sum non-parametric test was used to evaluate differences between the groups. The results showed that the DBA/2J, BALB/cJ, and 129P3/J inbred mouse strains are highly susceptible to RR, whereas A/J, C57BL/6J and SJL/J mice are much more resistant. The variation in the severity of RR associated with orthodontic force among different inbred strains of mice when age, gender, food, housing, and orthodontic force magnitude/duration are controlled support the hypothesis that susceptibility or resistance to RR associated with orthodontic force is a genetically influenced trait.

Acid Phosphatase↗

PubMed2005

Polymorphisms in the estrogen receptor beta (ESR2) gene are associated with bone mineral density in Caucasian men and women.

CONTEXT: A major determinant of osteoporotic fractures is peak bone mineral density (BMD), which is a highly heritable trait. Recently, we identified significant linkage for hip BMD in premenopausal sister pairs at chromosome 14q (LOD score = 3.5), where the estrogen receptor beta gene (ESR2) is located. OBJECTIVE: The objective of the study was to determine whether ESR2 polymorphisms are associated with normal BMD variation. DESIGN: This was a population-based genetic association study, using 11 single nucleotide polymorphisms (SNPs) distributed across the ESR2 gene. SETTING: The study was conducted at an academic research laboratory and medical center. PATIENTS AND OTHER PARTICIPANTS: A total of 411 healthy men (aged 18-61 yr) and 1291 healthy premenopausal women (aged 20-50 yr) living in Indiana participated in the study. INTERVENTION(S): There were no interventions. MAIN OUTCOME MEASURE(S): The main outcome measures were SNP genotype distributions and their association with BMD at the femoral neck and lumbar spine. RESULTS: Significant association of spine BMD was found with three SNPs in men and one SNP in women (P < or = 0.05). The conditional linkage analysis using the ESR2 haplotypes showed that the ESR2 gene accounts for, at most, 18% of the original linkage. CONCLUSIONS: ESR2 polymorphisms are significantly associated with bone mass in both men and women. However, the ESR2 gene is not entirely responsible for our original linkage, and an additional gene(s) in chromosome 14q contributes to the determination of BMD.

Adult↗

PubMed2004

Confirmation of linkage to chromosome 1q for peak vertebral bone mineral density in premenopausal white women.

Peak bone mineral density (BMD) is a highly heritable trait and is a good predictor of the risk of osteoporosis and fracture in later life. Recent studies have sought to identify the genes underlying peak BMD. Linkage analysis in a sample of 464 premenopausal white sister pairs detected linkage of spine BMD to chromosome 1q (LOD 3.6). An independent sample of 254 white sister pairs has now been genotyped, and it also provides evidence of linkage to chromosome 1q (LOD 2.5) for spine BMD. Microsatellite markers were subsequently genotyped for a 4-cM map in the chromosome 1q region in all available white sister pairs (n=938), and a LOD score of 4.3 was obtained near the marker D1S445. Studies in the mouse have also detected evidence of linkage to BMD phenotypes in the region syntenic to our linkage finding on chromosome 1q. Thus, we have replicated a locus on 1q contributing to BMD at the spine and have found further support for the region in analyses employing an enlarged sample. Studies are now ongoing to identify the gene(s) contributing to peak spine BMD in women.

Adult↗

PubMed2003

Genome-wide scan and conditional analysis in bipolar disorder: evidence for genomic interaction in the National Institute of Mental Health genetics initiative bipolar pedigrees.

BACKGROUND: In 1989 the National Institute of Mental Health began a collaborative effort to identify genes for bipolar disorder. The first 97 pedigrees showed evidence of linkage to chromosomes 1, 6, 7, 10, 16, and 22 (Nurnberger et al 1997). An additional 56 bipolar families have been genotyped, and the combined sample of 153 pedigrees studied. METHODS: Three hierarchical affection status models were analyzed with 513 simple sequence repeat markers; 298 were common across all pedigrees. The primary analysis was a nonparametric genome-wide scan. We performed conditional analyses based on epistasis or heterogeneity for five regions. RESULTS: One region, on 16p13, was significant at the genome-wide p <.05 level. Four additional chromosomal regions (20p12, 11p15, 6q24, and 10p12) showed nominally significant linkage findings (p </=.01). Conditional analysis assuming epistasis identified a significant increase in linkage at four regions. Families linked to 6q24 showed a significant increase in nonparametric logarithms of the odds (NPL) scores at 5q11 and 7q21. Epistasis also was observed between 20p12 and 13q21, and 16p13 and 9q21. CONCLUSIONS: The findings are presented in rank order of nominal significance. Several of these regions have been previously implicated in independent studies of either bipolar disorder or schizophrenia. The strongest finding is at 16p13 at D16S748 with an NPL of 3.3, there is evidence of epistasis between this locus and 9q21. Application of conditional analyses is potentially useful in larger sample collections to identify susceptibility genes of modest influence that may not be identified in a genome-wide scan aimed to identify single gene effects.

Bipolar Disorder↗

PubMed2003

Genetic predisposition to external apical root resorption.

External apical root resorption (EARR) can be an undesirable sequela of orthodontic treatment. Previous studies have suggested that EARR has a substantial genetic component. Linkage and association were examined between polymorphisms of the interleukin IL-1 (IL-1A and IL-1B) genes and EARR in 35 white American families. Buccal swab cells were collected for DNA isolation and analysis. The EARR in the maxillary central incisors, the mandibular central incisors, and the mesial and distal roots of the mandibular first molar were analyzed separately and together by using both linkage and association methods of analysis. Highly significant (P =.0003) evidence of linkage disequilibrium of IL-1B polymorphism with the clinical manifestation of EARR was obtained. The analysis indicates that the IL-1B polymorphism accounts for 15% of the total variation of maxillary incisor EARR. Persons homozygous for the IL-1B allele 1 have a 5.6 fold (95% CI 1.9-21.2) increased risk of EARR greater than 2 mm as compared with those who are not homozygous for the IL-1 beta allele 1. Data indicate that allele 1 at the IL-1B gene, known to decrease the production of IL-1 cytokine in vivo, significantly increases the risk of EARR. These findings are consistent with an interpretation of EARR as a complex condition influenced by many factors, with the IL-1B gene contributing an important predisposition to this common problem. Defining genetic contributions to EARR is an important factor in understanding the contribution of environmental factors, such as habits and therapeutic biomechanics.

Alleles↗

PubMed2003

Prenatal alcohol exposure: advancing knowledge through international collaborations.

Fetal alcohol syndrome (FAS) is a major public health issue that is evident on an international scale. The current article summarizes a meeting that was held in Valencia, Spain, in September 2001, that reviewed ongoing international collaborations and the prospects for new collaborative research. The attendees represented nine different countries and many different specialties. Following overviews of existing international collaborations in South Africa, Russia, and Chile, a number of topics for future work were discussed. Issues related to the diagnosis of FAS, its prevalence and how measures might be enhanced and standardized were presented, as obtaining consistency across populations is of prime importance. Another session discussed the current state of basic research and how collaborations in this area might be initiated. The neurobehavioral profile of FAS and how work in this area could be advanced and interpreted in light of findings with different populations generated considerable discussion. There was a review of brain imaging data in FAS and how this might be utilized in assisting the diagnosis of FAS and alcohol-related neurodevelopmental disorder (ARND). A presentation on the utilization of international collaborations in defining the role of genetics in the etiology of FAS was included. Finally, issues related to the prevention of FAS and how these issues might be modified based upon different populations were presented. International collaborations provide a wealth of resources for the study of FAS, and it was hoped that this meeting might better enhance the work ongoing in this area, and provide opportunities for future work.

Alcohol Drinking↗