Your search for: 'author:("Seshadri, Sudha")' has returned 38 results. (0.015s) Save search

Authors: Seshadri, Sudha

Article Type: Research Article

Abstract: Elevated plasma homocysteine (tHcy) concentrations have been associated with an increased risk of developing dementia and Alzheimer's disease (AD). It is not clear, however, if an elevation in tHcy concentration is a ‘risk factor’ with a direct pathophysiological role in the development of the disease or merely a ‘risk marker’ reflecting an underlying process such as oxidative stress responsible for both the high tHcy concentrations and the development of AD. Epidemiological studies have confirmed that elevations in plasma tHcy temporally precede the development of dementia and that there is a continuous, inverse linear relation between plasma tHcy concentrations and cognitive …performance in older persons. Several potential biological pathways that could mediate the observed association are briefly reviewed. In light of these data and the growing parallel interest in plasma tHcy as an emerging vascular risk factor there was considerable hope that vitamin therapy with folate, B12 and B6 , shown to lower plasma tHcy levels, could significantly reduce the risk of stroke and dementia permitting healthy brain aging. The results from recent trials addressing the secondary prevention of stroke and myocardial infarction trials have been disappointing. However, the role of vitamins and other homocysteine lowering treatments in the primary prevention of stroke and dementia, as well as their role in preserving cognition among persons with mild cognitive impairment and early dementia deserves to be fully pursued. Show more

Keywords: Alzheimer disease, dementia, homocysteine, plasma, risk factor

DOI: 10.3233/JAD-2006-9404

Citation: Journal of Alzheimer's Disease, vol. 9, no. 4, pp. 393-398, 2006

Authors: Dufouil, Carole | Seshadri, Sudha | Chêne, Geneviève

Article Type: Research Article

Abstract: There is growing evidence for the importance of cardiovascular risk factors in dementia development, including Alzheimer's disease. As cardiovascular risk profiles vary greatly by gender, with men suffering a greater burden of cardiovascular risk in midlife, this could lead to differences in dementia risk. To explore current evidence on the association between components of the cardiovascular risk profile and dementia risk in women and men, we reviewed all studies reporting the risk of dementia associated with cardiovascular risk factors stratified by gender and found 53 eligible articles out of over 4,000 published since the year 2000. Consistent results were found: …1) for exposures acting specifically in women: Overweight/obesity (harmful) and physical activity (protective), and 2) for exposures acting similarly in women and men: Moderate alcohol (protective) and hypertension, diabetes, and depression (harmful). A modified effect of tobacco or high cholesterol/statin use remained controversial. Available data do not allow us to assess whether selection of men with healthier cardiovascular profile (due to cardiovascular death in midlife) could lead in late life either to a difference in the distribution of risk factors or to a differential effect of these risk factors by gender. We recommend that results on dementia risk factors, especially cardiovascular ones, be reported systematically by gender in all future studies. More generally, as cardiovascular risk profiles evolve over time, more attention needs to be paid to the detection and correction of cardiovascular risk factors, as early as possible in the life course, and as actively in women as in men. Show more

Keywords: Alzheimer's disease, cardiovascular diseases, dementia, prevention, risk factors, women

DOI: 10.3233/JAD-141629

Citation: Journal of Alzheimer's Disease, vol. 42, no. s4, pp. S353-S363, 2014

Authors: Peloso, Gina M. | Beiser, Alexa S. | Destefano, Anita L. | Seshadri, Sudha

Article Type: Research Article

Abstract: Epidemiological and genetic studies have pointed to the role of cholesterol in Alzheimer’s disease (AD). We explored the interaction of a genetic risk score (GRS) of AD risk alleles with mid-life plasma lipid levels (LDL-C, HDL-C, and triglycerides) on risk for AD in the Framingham Heart Study (FHS). Mid-life (between the ages of 40–60 years old) lipid levels were obtained from individuals in the FHS Original and Offspring cohorts (157 cases and 2,882 controls) with genetic data and AD status available. Cox proportional hazards regression was performed to test the interaction between mid-life lipid levels and an AD GRS, as …well as the individual contributing SNPs, on risk of incident AD adjusting for age, sex, and cohort. We found a significant interaction between a GRS of AD loci and log triglyceride levels on risk of clinical AD (p  = 0.006), but no interaction of the GRS with HDL-C (p  = 0.458) or LDL-C (p  = 0.366). We then tested the interaction between the individual SNPs contributing to the GRS and log triglycerides. We found two SNPs that had interactions with triglycerides on AD risk that reached a p -value < 0.05 (rs11218343 and APOE ɛ 4). The association between some AD SNPs and risk of AD may be modified by triglyceride levels. Furthermore, sequential testing of a GRS with a set of traits on disease followed by testing individual SNPs for interaction provides a framework for narrowing the associations that need to be tested for interaction analyses. Replication is needed to confirm these findings. Show more

Keywords: Alzheimer’s disease, association studies in genetics, cohort studies, risk factors in epidemiology

DOI: 10.3233/JAD-180751

Citation: Journal of Alzheimer's Disease, vol. 66, no. 3, pp. 1275-1282, 2018

Authors: Weinstein, Galit | Wolf, Philip A. | Beiser, Alexa S. | Au, Rhoda | Seshadri, Sudha

Article Type: Review Article

Abstract: The study of Alzheimer's disease (AD) in the Framingham Heart Study (FHS), a multi-generational, community-based population study, began nearly four decades ago. In this overview, we highlight findings from seven prior publications that examined lifetime risk estimates for AD, environmental risk factors for AD, circulating and imaging markers of aging-related brain injury, and explorations on the genetics underlying AD. First, we describe estimations of the lifetime risk of AD. These estimates are distinguished from other measures of disease burden and have substantial public health implications. We then describe prospective studies of environmental AD risk factors: one examined the association between …plasma levels of omega-3 fatty-acid and risk of incident AD, the other explored the association of diabetes to this risk in subsamples with specific characteristics. With evidence of inflammation as an underlying mechanism, we also describe findings from a study that compared the effects of serum cytokines and spontaneous production of peripheral blood mononuclear cell cytokines on AD risk. Investigating AD related endophenotypes increases sensitivity in identifying risk factors and can be used to explore pathophysiologic pathways between a risk factor and the disease. We describe findings of an association between large volume of white matter hyperintensities and a specific pattern of cognitive deficits in non-demented participants. Finally, we summarize our findings from two genetic studies: The first used genome-wide association (GWA) and family-based association methods to explore the genetic basis of cognitive and structural brain traits. The second is a large meta-analysis GWA study of AD, in which novel loci of AD susceptibility were found. Together, these findings demonstrate the FHS multi-directional efforts in investigating dementia and AD. Show more

Keywords: Alzheimer's disease, cerebrovascular disorders, cohort studies, genetic variation, risk factors

DOI: 10.3233/JAD-2012-129040

Citation: Journal of Alzheimer's Disease, vol. 33, no. s1, pp. S439-S445, 2013

Authors: Teixeira, Antonio L. | Salem, Haitham | Martins, Lais B. | Gonzales, Mitzi M. | Seshadri, Sudha | Suchting, Robert

Article Type: Research Article

Abstract: Background: Apathy is among the most frequent neuropsychiatric syndromes in Alzheimer’s disease (AD). Objective: To determine the prevalence of apathy and the associated clinical and laboratorial parameters (focus on inflammatory biomarkers) in patients with dementia enrolled at the Texas Alzheimer’s Research and Care Consortium (TARCC) study. Methods: This is a cross-sectional analysis of TARCC baseline. Participants were evaluated through different clinical tools, including the Mini-Mental State Examination (MMSE) and the Lawton-Brody Instrumental Activities of Daily Life (IADL)/Physical Self-Maintenance Scale (PSMS). Apathy was defined by a positive response to the respective item in the Neuropsychiatric Inventory–Questionnaire applied to caregivers. Serum levels …of 16 biomarkers were determined by HumanMap multiplex immunoassay. Comparisons between apathy versus non-apathy groups were carried out with non-parametric tests. Logistic regression and the least absolute shrinkage and selection operator (LASSO) were used to separately model apathy as a function of each biomarker, adjusted for the potential confounders. Results: From 1,319 patients with AD (M/F: 579/740, mean age ± SD: 75.3 ± 8.4), 373 (28.3%) exhibited apathy. When categorized according to the presence of apathy, the groups had significant differences in sex, diabetes diagnosis, and tobacco use. The apathy group also had worse cognitive performance and daily functioning than the non-apathy group as assessed, respectively, by MMSE and IADL/PSMS. Higher levels of interleukin-6, interleukin-10, and leptin were associated with higher odds of apathy. Conclusion: Apathy is associated with cognitive and functional status in AD. The association between apathy and peripheral inflammatory mediators deserves further investigation. Show more

Keywords: Alzheimer’s disease, apathy, inflammation, interleukin-6, interleukin-10

DOI: 10.3233/JAD-215314

Citation: Journal of Alzheimer's Disease, vol. 86, no. 1, pp. 403-411, 2022

Authors: Salem, Haitham | Suchting, Robert | Gonzales, Mitzi M. | Seshadri, Sudha | Teixeira, Antonio L.

Article Type: Research Article

Abstract: Background: Apathy is among the neuropsychiatric symptoms frequently observed in people with cognitive impairment. It has been postulated to be a potential predictor of conversion from mild cognitive impairment (MCI) to Alzheimer’s disease (AD). Objective: To detect conversion rates from MCI to AD, and to determine the effect of apathy on the progression to AD in patients with MCI enrolled in the Texas Alzheimer’s Research and Care Consortium (TARCC) cohort. Methods: Apathy was determined by a positive response to the respective item in the Neuropsychiatric Inventory –Questionnaire (NPI-Q) completed by family members or caregivers. The final dataset included 2,897 observations …from 1,092 individuals with MCI at the baseline. Kaplan-Meier survival curves were estimated to provide indices of the probability of conversion to AD over time across all individuals as well as between those with and without apathy. Cox proportional hazards regression measured the hazard associated with apathy and several other predictors of interest. Results: Over a period of 8.21 years, 17.3% of individuals had conversion from MCI to AD (n  = 190 of 1,092 total individuals) across observations. The median time-to-conversion across all participants was 6.41 years. Comparing individuals with apathy (n  = 158) versus without apathy (n  = 934), 36.1% and 14.2% had conversion to AD, respectively. The median time-to-conversion was 3.79 years for individuals with apathy and 6.83 years for individuals without apathy. Cox proportional hazards regression found significant effects of several predictors, including apathy, on time-to-conversion. Age and cognitive performance were found to moderate the relationship between apathy and time-to-conversion. Conclusions: Apathy is associated with progression from MCI to AD, suggesting that it might improve risk prediction and aid targeted intervention delivery. Show more

Keywords: Alzheimer’s disease, apathy, mild cognitive impairment, neuropsychiatric symptoms

DOI: 10.3233/JAD-220826

Citation: Journal of Alzheimer's Disease, vol. 92, no. 1, pp. 129-139, 2023

Authors: Lebowitz, Brian K. | Weinstein, Cheryl | Beiser, Alexa | Seshadri, Sudha | Wolf, Philip A. | Auerbach, Sandford | Au, Rhoda

Article Type: Research Article

Abstract: Although neuropsychological tests are commonly used in the evaluation of possible mild cognitive impairment (MCI), poor test scores may be indicative of factors other than neurological compromise. The current study assessed the role of lifelong reading disorder on MCI classification. Community dwelling older adults with a suspected developmental reading disorder were identified by inference based on reading test performance. Individuals with a suspected reading disorder were significantly more likely to perform at a level consistent with MCI on several commonly used neuropsychological tests. The findings suggest a relationship between a history of reading disorder and MCI classification.

Keywords: Alzheimer’s disease, cognition, dyslexia, learning disorders, memory disorders, mild cognitive impairment, neuropsychological tests

DOI: 10.3233/JAD-150543

Citation: Journal of Alzheimer's Disease, vol. 50, no. 1, pp. 41-45, 2016

Authors: Adams, Stephanie L. | Benayoun, Laurent | Tilton, Kathy | Mellott, Tiffany J. | Seshadri, Sudha | Blusztajn, Jan Krzysztof | Delalle, Ivana

Article Type: Research Article

Abstract: The pathophysiology of Alzheimer’s disease (AD) includes signaling defects mediated by the transforming growth factor β—bone morphogenetic protein—growth and differentiation factor (TGFβ-BMP-GDF) family of proteins. In animal models of AD, administration of BMP9/GDF2 improves memory and reduces amyloidosis. The best characterized type I receptor of BMP9 is ALK1. We characterized ALK1 expression in the hippocampus using immunohistochemistry. In the rat, ALK1 immunoreactivity was found in CA pyramidal neurons, most frequently and robustly in the CA2 and CA3 fields. In addition, there were sporadic ALK1-immunoreactive cells in the stratum oriens, mainly in CA1. The ALK1 expression pattern in human hippocampus was …similar to that of rat. Pyramidal neurons within the CA2, CA3, and CA4 were strongly ALK1-immunoreactive in hippocampi of cognitively intact subjects with no neurofibrillary tangles. ALK1 signal was found in the axons of alveus and fimbria, and in the neuropil across CA fields. Relatively strongest ALK1 neuropil signal was observed in CA1 where pyramidal neurons were occasionally ALK1-immunoractive. As in the rat, horizontally oriented neurons in the stratum oriens of CA1 were both ALK1- and GAD67-immunoreactive. Analysis of ALK1 immunoreactivity across stages of AD pathology revealed that disease progression was characterized by overall reduction of the ALK1 signal in CA3 in advanced, but not early, stages of AD. These data suggest that the CA3 pyramidal neurons may remain responsive to the ALK1 ligands, e.g., BMP9, during initial stages of AD and that ALK1 may constitute a therapeutic target in early and moderate AD. Show more

Keywords: ACVRL1, ALK1, CA1, CA3, GAD67, hippocampus, immunohistochemistry

DOI: 10.3233/JAD-171065

Citation: Journal of Alzheimer's Disease, vol. 63, no. 4, pp. 1433-1443, 2018

Authors: Adams, Stephanie L. | Benayoun, Laurent | Tilton, Kathy | Chavez, Olivia R. | Himali, Jayandra J. | Blusztajn, Jan Krzysztof | Seshadri, Sudha | Delalle, Ivana

Article Type: Research Article

Abstract: Genome-wide association studies (GWAS) identified susceptibility loci associated with decreased hippocampal volume, and found hippocampal subfield-specific effects at MSRB3 (methionine sulfoxide reductase-B3). The MSRB3 locus was also linked to increased risk for late onset Alzheimer’s disease (AD). In this study, we uncovered novel sites of MsrB3 expression in CA pyramidal layer and arteriolar walls by using automated immunohistochemistry on hippocampal sections from 23 individuals accompanied by neuropathology reports and clinical dementia rating scores. Controls, cognitively intact subjects with no hippocampal neurofibrillary tangles, exhibited MsrB3 signal as distinct but rare puncta in CA1 pyramidal neuronal somata. In CA3, however, MsrB3-immunoreactivity was …strongest in the neuropil of the pyramidal layer. These patterns were replicated in rodent hippocampi where ultrastructural and immunohistofluorescence analysis revealed MsrB3 signal associated with synaptic vesicles and colocalized with mossy fiber terminals. In AD subjects, the number of CA1 pyramidal neurons with frequent, rather than rare, MsrB3-immunoreactive somatic puncta increased in comparison to controls. This change in CA1 phenotype correlated with the occurrence of AD pathological hallmarks. Moreover, the intensity of MsrB3 signal in the neuropil of CA3 pyramidal layer correlated with the signal pattern in neurons of CA1 pyramidal layer that was characteristic of cognitively intact individuals. Finally, MsrB3 signal in the arteriolar walls in the hippocampal white matter decreased in AD patients. This characterization of GWAS-implicated MSRB3 protein expression in human hippocampus suggests that patterns of neuronal and vascular MsrB3 protein expression reflect or underlie pathology associated with AD. Show more

Keywords: Alzheimer’s disease, CA1, CA3, hippocampal arterioles, MsrB3, synaptic vesicles

DOI: 10.3233/JAD-170459

Citation: Journal of Alzheimer's Disease, vol. 60, no. 1, pp. 43-56, 2017

Authors: Nishtala, Arvind | Himali, Jayandra J. | Beiser, Alexa | Murabito, Joanne M. | Seshadri, Sudha | Wolf, Philip A. | Au, Rhoda

Article Type: Research Article

Abstract: Midlife cardiovascular risk, hypertension (HTN) in particular, has been related cross-sectionally to poorer neuropsychological (NP) performance in middle age and older adults. This study investigated whether a similar relationship persists between midlife HTN or systolic blood pressure (SBP) and NP performance approximately 30 years later. 378 Framingham stroke and dementia-free Original cohort participants, with HTN and SBP ascertained between 50–60 years of age (mean age 55 ± 1, 65% women), were administered a NP assessment at age ≥80 years. Tests included Logical Memory, Visual Reproduction, Paired Associate, Hooper Visual Organization Test, Trail Making A & B, Digit Span Forward and …Backward, Controlled Word Association Test (COWAT), and Similarities. Multivariable linear regression, adjusted for age, time interval between risk factor and NP testing, gender, and premorbid intelligence, assessed association between midlife HTN/SBP and NP outcomes. Midlife HTN was not significantly associated with NP outcome measures. Midlife SBP was associated with poorer Digit Span Forward and COWAT performance (p  <  0.05). No significant interaction of age on HTN/SBP to NP associations was found. There was a significant interaction between ApoE4 status and SBP in their effects on COWAT (pinteraction  = 0.074); SBP was negatively associated with COWAT only in those with the ApoE4 allele (p  = 0.025). While midlife HTN is not associated with late life cognitive impairment, midlife SBP is related to late life attention and verbal fluency impairments, particularly among ApoE4+ individuals. These results offer insight into processes that are operative in the absence of overt cognitive impairment and dementia. Show more

DOI: 10.3233/JAD-141881

Citation: Journal of Alzheimer's Disease, vol. 47, no. 1, pp. 197-204, 2015