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Biomedical subjects

P M Doraiswamy

Publications and source records attributed to P M Doraiswamy.

At least 19 recordsLinked to original sources
PubMed2006

Lack of association between UBQLN1 and Alzheimer disease.

Alzheimer disease (AD) is heterogeneous and complex with a strong genetic diathesis. It is the most common cause of dementia affecting the elderly. Linkage studies [Kehoe et al., 1999; Hum Mol Genet 8: 237-245]; [Pericak-Vance et al., 2000; Exp Gerontol 35: 1343-1352]; [Myers et al., 2002; Am J Med Genet 114: 235-244]; [Blacker et al., 2003; Hum Mol Genet 12: 23-32] identified chromosome 9q as a region containing a possible AD candidate gene. Functional protein studies [Mah et al., 2000; J Cell Biol 151: 847-862]; [Ko et al., 2002; J Biol Chem 277: 35386-35392] identified the UBQLN1 gene on chromosome 9q that encodes ubiquilin as a likely candidate for a role in late-onset AD pathogenesis. A recent family-based study by [Bertram et al., 2005; N Engl J 352: 884-894] reported genetic association and expression evidence for a putative AD risk allele of an intronic single nucleotide polymorphism (SNP) within the UBQLN1 gene. In this study, we comprehensively assessed whether any of seven polymorphisms located across the UBQLN1 gene are associated with AD in another large family-based data set and an independent case-control data set. We found no significant association of AD risk with any of the seven SNPs genotyped (including those SNPs previously reported by Bertram et al.) in either the family-based or case-control data set. Age-specific analyses and analyses conditional on Apolipoprotein E (ApoE) genotype and sex also revealed no significant associations to AD risk in either data set. Using age at onset (AAO) as a quantitative trait revealed a modest age modifying association; however, the results were inconsistent between the data sets. Our results suggest that UBQLN1 variants do not increase risk for AD in these data.

Adaptor Proteins, Signal Transducing↗
PubMed2006

Hippocampal atrophy confounds template-based functional MR imaging measures of hippocampal activation in patients with mild cognitive impairment.

BACKGROUND AND PURPOSE: Functional MR imaging has been used to study patterns of hippocampal activation that distinguish pathologic from normal memory loss in the elderly population. Our objective was to assess whether hippocampal atrophy confounds measurements of hippocampal activation in subjects with mild cognitive impairment (MCI). METHODS: Twenty subjects with MCI and 20 elderly control subjects with objectively normal memory were studied at 4T during a face-name paradigm designed to activate the hippocampus. Hippocampal activation was measured using 2 separate approaches: applying a preset region of interest (ROI) in standardized template space and applying a manually drawn ROI in native subject space. Pearson correlation coefficients were calculated to compare group-dependent relationships between hippocampal volume and activation. Analysis of covariance (ANCOVA) was performed to assess group differences in hippocampal activation during encoding and retrieval. Age and hippocampal volume were included as covariates, as was a term for the interaction between hippocampal volume and group. RESULTS: When hippocampal activation was measured by the template-based method, the correlation coefficient in the right hippocampus of subjects with MCI but not control subjects during retrieval differed significantly from zero. There was a significant (P < .05) group-by-volume interaction in the ANCOVA model. No significant correlations or interactions were demonstrated when activation was measured in native subject space with manually drawn ROIs. CONCLUSION: Our findings suggest a potential confounding relationship between hippocampal volume and activation for subjects with MCI in template-based analyses. Template-based measures of hippocampal activation that do not adequately account for hippocampal atrophy should be used with caution in patients with MCI.

Aged↗
PubMed2004

In vivo amyloid imaging in Alzheimer's disease.

Targeted approaches to therapy for Alzheimer's disease have evolved based on detailed understanding of the genetic, molecular biologic, and neuropathologic basis of the disease. Given the potential for greater treatment efficacy in the earlier stages of the disease, the notion of early diagnosis has become more relevant. Current clinical and imaging diagnostic approaches lack reliability in the preclinical and prodromal phases of the disease. We review emerging studies on imaging of the molecular substrate of the disease, most notably the amyloid peptide, which hope to increase early diagnostic efficacy. We offer a brief overview of the demographics, diagnostic criteria, and current imaging tests, followed by a review of amyloid biology and developments in cerebral amyloid imaging yielded by recent in vitro, in vivo and human studies.

Alzheimer Disease↗
PubMed2001

Bupropion SR in the naturalistic treatment of elderly patients with major depression.

INTRODUCTION: Bupropion immediate release (IR) and bupropion sustained release (SR) are frequently used to treat geriatric depression, as they have few cardiovascular, gastrointestinal and sexual adverse effects. We sought to examine the efficacy and dosing patterns of bupropion in a naturalistic cohort of elderly subjects with major depression (MD). METHODS: 31 elderly ( > 60 years) patients with unipolar MD (DSM-IV) who were enrolled in Duke's Mental Health Clinical Research Center for the Study of Depression in Later Life were prescribed bupropion SR or IR, alone or in combination with other antidepressant agents, for 12 weeks. Montgomery-Asberg depression rating scale (MADRS) scores and clinical global impression (CGI) severity scores were used to define response. RESULTS: 74% (23/31) of the sample were responders (MADRS < 15) and 53% (16/30) achieved a partial (CGI = 2) or complete (CGI = 1) remission of MD at week 12. Among patients treated with bupropion SR monotherapy, the mean (range) maximal daily dose achieved was 240 mg (150-400 mg). Among those treated with bupropion IR, the mean (range) maximum daily dose achieved was 258 mg (150-450 mg). In subjects on monotherapy, 67% (10/15) of MD subjects were responders (MADRS < 15) and 50% (7/14) achieved full or partial remission. Response rates did not differ statistically among those with high and low medical comorbidity. CONCLUSIONS: In this naturalistic 12-week study, geriatric MD patients with high and low medical comorbidity responded well to bupropion and bupropion SR. In elderly patients, four to eight week acute treatment periods may be insufficient. Our findings suggest that nearly 50% of elderly depressed subjects at a tertiary center may need combination therapy over the course of their illness. Controlled randomized studies to establish the long-term efficacy and optimal dose of the newer antidepressants in geriatric depression are urgently needed.

Administration, Oral↗
PubMed2001

Clinical and treatment response characteristics of late-life depression associated with vascular disease: a pooled analysis of two multicenter trials with sertraline.

1. The safety and efficacy of sertraline in the treatment of moderate-to-severe major depression in elderly outpatients, aged 60 years and older, with comorbid vascular disease was evaluated. 2. An analysis of the pooled results for the sertraline treatment group drawn from two prospective, randomized, double-blind studies (sertraline vs. fluoxetine, and sertraline vs. nortriptyline) was done. Patients were retrospectively categorized into one of 3 clinical groups: 1) patients with a current diagnosis of hypertension but no other past or present cardiovascular illness (HTN), 2) patients reporting a current or past history of cardiovascular illness, but excluding hypertension (VASC), and 3) patients with no hypertension, and no other comorbid vascular illness (NoVASC). Patients received 12-3. weeks of double-blind treatment with sertraline in flexible daily doses in the range of 50 - 150 mg (in the nortriptyline comparator trial) or 50 - 100 mg (in the fluoxetine comparator trial). 4. Sertraline treatment yielded comparable levels of response in all 3 groups (response criterion: CGI-much or very much improved) at treatment endpoint on both a completer analysis (HTN, 86%; VASC, 89%; NoVASC, 77%) and significantly higher response rates on a 12-week endpoint analysis (HTN, 74%; VASC, 69%; NoVASC, 58%; p < 0.05). Sertraline treatment was well-tolerated, with no between-group differences in rates of adverse events, or in discontinuation due to adverse events. Patients taking 5 or more concomitant medications showed no difference, when compared with patients taking none-or-one concomitant medication, either in rates of adverse events, or in discontinuation due to adverse events. 5. Sertraline was found to be a safe, well-tolerated, and effective as an antidepressant in elderly patients suffering from hypertension and other forms of vascular comorbidity.

Age of Onset↗
PubMed2001

Olanzapine-associated severe hyperglycemia, ketonuria, and acidosis: case report and review of literature.

Olanzapine has been associated with insulin resistance and new-onset diabetes mellitus. A 27-year-old African-American man developed new-onset severe hyperglycemia-glucose 1240 mg/dl, with ketonuria and acidosis, but no weight gain-2 years after starting olanzapine. Although his diabetes was stabilized with insulin, his family had difficulty monitoring his therapy, and insulin was discontinued. Subsequent monotherapy with pioglitazone stabilized the patient's glucose levels, allowing him to continue taking olanzapine. Health care professionals should be aware of links between olanzapine and diabetes mellitus and of the potential for delayed recognition of complications associated with diabetes in patients who are psychotic. Insulin poses additional problems because families of patients with schizophrenia have to deal with compliance and risk of accidental or suicidal overdose. This case and others described in the literature illustrate such dilemmas and highlight the need to further study links connecting diabetes, insulin resistance, and olanzapine. Further research to determine proportionality and risk differences among various atypical antipsychotics also is warranted.

Adult↗
PubMed2001

Contemporary management of comorbid anxiety and depression in geriatric patients.

Anxiety and depression in elderly people are major public health problems in the United States. Recognition and treatment of these conditions will likely gain more attention in the next 30 to 50 years because of the projected growth of the geriatric population. As in many younger patients, the most common presentation of anxiety in elderly patients is comorbid anxiety and depression. Although age is not a risk factor for either anxiety or depression, factors associated with aging--such as increased medical burdens and loss of independence--are substantial risk factors for development of these conditions. Moreover, there is a close association in older people between untreated mental illness and exacerbation of physical illness. Some of the newer antidepressants are more appropriate long-term options for the treatment of comorbid anxiety and depression than either benzodiazepines or tricyclic antidepressants. The newer antidepressants can decrease symptoms, improve quality of life, and potentially promote healthier outcomes in geriatric patients who have comorbid anxiety and depression and/or comorbid mental and physical illness.

Age Factors↗
PubMed2001

Quality of life in geriatric depression: a comparison of remitters, partial responders, and nonresponders.

The authors examined patterns of improvement in quality of life (QOL) in elderly patients with recurrent major depression (MDD) after acute treatment. One hundred elderly (age 60-88 years) patients with recurrent MDD were randomized to receive either bupropion sustained-release (100 mg-300 mg/day) or paroxetine (10 mg-40 mg/day) for 6 weeks. Treatment with both paroxetine and bupropion was associated with improvements in QOL. Lower perceived Physical- and Social-Functioning QOL ratings at baseline were associated with lower treatment response. Improvement in depression symptom ratings correlated significantly with improvement in QOL on many domains, but accounted for less than one-quarter of the total variance. Remitters showed significantly (P<0.001) greater improvement than both Partial Responders and Nonresponders on various measures. Findings support the importance of treating elderly depressed patients to full remission to maximize impact on both emotional and physical QOL domains.

Aged↗
PubMed2001

Informant-rated cognitive symptoms in normal aging, mild cognitive impairment, and dementia. Initial development of an informant-rated screen (Brief Cognitive Scale) for mild cognitive impairment and dementia.

An informant-rated cognitive screen may have the potential to reliably help detect early dementia. A valuable scale should have good interitem associations and strong reliability when tested in groups with and without cognitive impairment. Our scale, the Brief Cognitive Scale (BCS), consists of 18 questions designed to assess cognitive function that affects everyday activities. Each question is coded with one of four levels, ranging from no impairment to severe impairment. We administered this screen to 120 subjects: 26 controls, 28 with a diagnosis of mild cognitive impairment (MCI), and 66 with a diagnosis of dementia. In addition, we administered a Folstein Mini-Mental Status Examination (MMSE) to each subject. Our results showed that the BCS scores were lowest in the control group and highest in the dementia group. In our sample, this scale was effective at discriminating between subjects with no cognitive impairment, MCI, and dementia. However, the scale needs further refinement before it can be employed in a clinical setting.

Aged↗
PubMed2000

Hippocampal sulcal cavities on MRI: relationship to age and apolipoprotein E genotype.

Hippocampal sulcal cavities are usually considered incidental findings on brain MRI. In a group of 92 elderly volunteers, the authors graded the number and size of hippocampal sulcal cavities with brain MRI to obtain a cavity score. Cavity scores increased with age, and were higher in subjects carrying the APOE epsilon4 or epsilon2 alleles than in subjects with the epsilon3/3 genotype. Age-related morphologic changes in the hippocampus may be mediated by the APOE genotype.

Age Factors↗
PubMed2000

Current and future treatments for cognitive deficits in dementia.

In this article, we primarily focus on the treatment approaches currently marketed and in advanced stages of development for Alzheimer's disease (AD). Amyloid plaques and neurofibrillary tangles remain the pathologic hallmarks of AD, and much progress has been made in unraveling the molecular biology of these changes. In addition, there is also intense research into inflammatory and oxidative mechanisms as well as vascular and neurochemical alterations in AD. Therapies targeted at these mechanisms are discussed.

Aged↗
PubMed2000

Efficacy and safety of St. John's wort for the treatment of major depression.

OBJECTIVE: Extracts of St. John's wort have been widely used in the treatment of depression. Our aim was to review information related to the efficacy and safety of St. John's wort as an antidepressant. DATA SOURCES: Primary and review articles were identified by a search of Medline (1960 to February 2000) and through secondary sources. STUDY SELECTION: All the articles identified from the data sources were evaluated and all relevant information was included in this review. The pharmacokinetics, mechanism of action, efficacy, side effects and drug interactions of St. John's wort have been examined in various studies. CONCLUSION: St. John's wort is a promising investigational antidepressant, but the data are not yet sufficient to accept hypericum as a first line antidepressant preparation for treatment of depression. Besides the need for dose standardization and adequate trial lengths, there is a need for studies in severely depressed patients and long-term studies to assess the risk of relapse and recurrence.

Antidepressive Agents↗
PubMed2000

Magnetic resonance spectroscopy in Alzheimer's disease: focus on N-acetylaspartate.

This paper reviews published post-mortem brain and in-vivo proton magnetic resonance spectroscopy (1H-MRS) studies in Alzheimer's disease (AD) and focuses on the emerging role of N-acetylaspartate (NAA) as a prognostic marker of neuronal function. Post-mortem brain studies have reported significantly lower NAA levels in AD brains than in control brains, and some have correlated the low levels with neuropathological findings (i.e. amyloid plaques and neurofibrillary tangles). Similarly, almost all published in-vivo studies have reported lower NAA levels in AD patients compared to elderly controls. While some studies have found changes in metabolite levels that were considered useful for the diagnosis of AD, most have found that 1H-MRS provided little or no advantages over other, more common diagnostic tools. Instead, recent studies in AD and other neuropsychiatric disorders suggest that NAA may be more useful as a prognostic marker for monitoring neurodegeneration, stabilization, or improvement, and for evaluating therapeutic response to novel drugs.

Aged↗
PubMed2000

Reboxetine: a selective norepinephrine reuptake inhibitor for the treatment of depression.

OBJECTIVE: To review the pharmacology, pharmacokinetics, efficacy, and tolerability of reboxetine in the treatment of major depressive illness. DATA SOURCES: A MEDLINE search restricted to English-language literature was conducted (1966 to July 1999). Abstracts and posters presented at meetings were also reviewed. DATA EXTRACTION/STUDY SELECTION: Studies currently available were conducted in Europe. Data from clinical trials were reviewed to gather information specific to efficacy analysis, pharmacokinetic parameters, tolerability profiles, and drug-drug interactions. Information on reboxetine was compared with other antidepressant therapies when appropriate data were available. DATA SYNTHESIS: Reboxetine is a selective norepinephrine reuptake inhibitor shown to be an effective agent in the treatment of major depressive illness. In clinical trials, reboxetine was effective in decreasing mean total scores of the Hamilton Rating Scale for Depression in adult populations. Improvements were similar between reboxetine and desipramine and imipramine, as well as fluoxetine. Reboxetine is relatively well tolerated, with insomnia, sweating, constipation, and dry mouth being commonly reported adverse events. Hypotension and urinary hesitancy occur at lower rates than with the tricyclics, and compared with fluoxetine, reboxetine is associated with lower rates of nausea, somnolence, and diarrhea. Dosage adjustments may be appropriate in elderly patients and those with renal and hepatic impairment. CONCLUSIONS: Reboxetine has received two letters of approval from the Food and Drug Administration for the treatment of major depression in adults. Upon completion of an additional US clinical study, reboxetine is likely to become a first-line agent in the management of depressive illness and a promising alternative for patients who have failed treatment with or do not tolerate serotonergic antidepressants.

Adrenergic Uptake Inhibitors↗