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P Murali Doraiswamy

Publications and source records attributed to P Murali Doraiswamy.

At least 19 recordsLinked to original sources
PubMed2007

Coenzyme Q10: a review of its promise as a neuroprotectant.

Coenzyme Q10 (CoQ10) is a powerful antioxidant that buffers the potential adverse consequences of free radicals produced during oxidative phosphorylation in the inner mitochondrial membrane. Oxidative stress, resulting in glutathione loss and oxidative DNA and protein damage, has been implicated in many neurodegenerative disorders, including Alzheimer's disease, Parkinson's disease, and Huntington's disease. Experimental studies in animal models suggest that CoQ10 may protect against neuronal damage that is produced by ischemia, atherosclerosis and toxic injury. Though most have tended to be pilot studies, there are published preliminary clinical trials showing that CoQ10 may offer promise in many brain disorders. For example, a 16-month randomized, placebo-controlled pilot trial in 80 subjects with mild Parkinson's disease found significant benefits for oral CoQ10 1,200 mg/day to slow functional deterioration. However, to date, there are no published clinical trials of CoQ10 in Alzheimer's disease. Available data suggests that oral CoQ10 seems to be relatively safe and tolerated across the range of 300-2,400 mg/day. Randomized controlled trials are warranted to confirm CoQ10's safety and promise as a clinically effective neuroprotectant.

Alzheimer Disease↗
PubMed2006

Predicting memory decline in normal elderly: genetics, MRI, and cognitive reserve.

Major predictors of Alzheimer's disease (AD) include apolipoprotein E (APOE)-epsilon4, hippocampal atrophy on magnetic resonance imaging (MRI), and memory dysfunction prior to diagnosis. We examined 159 normal elderly subjects with MRI and the California Verbal Learning Test (CVLT); 84 returned for longitudinal follow-up 5 years later. Analyses at baseline revealed significant variance in hippocampal volume accounted for by cerebral volume and age but not by APOE isoform. However, interactions involving APOE isoform and laterality were observed. As hypothesized, an APOE x time interaction was revealed for CVLT long-delay free recall: APOE-epsilon3/4 subjects had significantly poorer performance than APOE-epsilon3/3 subjects at follow-up. Forward stepwise multiple regression analysis predicting follow-up long-delay free recall selected baseline recall, followed by number of APOE-epsilon4 alleles, followed by left-hippocampal volume. Age and sex did not enter into the model. We conclude that APOE-epsilon4 predicts longitudinal memory decline in healthy controls and that MRI morphometry of hippocampus adds slightly to predictive value.

Aged↗
PubMed2006

Parsing the genetic heterogeneity of chromosome 12q susceptibility genes for Alzheimer disease by family-based association analysis.

Previous linkage studies have suggested that chromosome 12 may harbor susceptibility genes for late-onset Alzheimer disease (LOAD). No risk genes on chromosome 12 have been conclusively identified yet. We have reported that the linkage evidence for LOAD in a 12q region was significantly increased in autopsy-confirmed families particularly for those showing no linkage to alpha-T catenin gene, a LOAD candidate gene on chromosome 10 [LOD score increased from 0.1 in the autopsy-confirmed subset to 4.19 in the unlinked subset (optimal subset); p<0.0001 for the increase in LOD score], indicating a one-LOD support interval spanning 6 Mb. To further investigate this finding and to identify potential candidate LOAD risk genes for follow-up analysis, we analyzed 99 single nucleotide polymorphisms in this region, for the overall sample, the autopsy-confirmed subset, and the optimal subset, respectively, for comparison. We saw no significant association (p<0.01) in the overall sample. In the autopsy-confirmed subset, the best finding was obtained in the activation transcription factor 7 (ATF7) gene (single-locus association, p=0.002; haplotype association global, p=0.007). In the optimal subset, the best finding was obtained in the hypothetical protein FLJ20436 (FLJ20436) gene (single-locus association, p=0.0026). These results suggest that subset and covariate analyses may be one approach to help identify novel susceptibility genes on chromosome 12q for LOAD.

Alzheimer Disease↗
PubMed2006

Mild cognitive impairment: evaluation with 4-T functional MR imaging.

PURPOSE: To prospectively assess abnormalities in brain activation patterns during encoding and retrieval in subjects with mild cognitive impairment by using 4-T functional magnetic resonance (MR) imaging. MATERIALS AND METHODS: The institutional review board approved this HIPAA-compliant study; all subjects gave written informed consent. Twenty patients with mild cognitive impairment (12 men, eight women; mean age, 75.0 years +/- 7.6 [standard deviation]) and 20 elderly control subjects (nine men, 11 women; mean age, 71.2 years +/- 4.5) underwent functional MR imaging at 4 T during a novel-versus-familiar face-name encoding-retrieval task. The magnitude of blood oxygen level-dependent brain responses across the entire brain were compared within and between subjects with mild cognitive impairment and control subjects by using a voxelwise random-effects model. A one-sample t test was used for within-group analysis; an analysis-of-covariance model (with age as a covariate) was used for between-group analysis. RESULTS: Brain regions activated by the task (prefrontal, medial temporal, and parietal regions) during encoding were similar to those activated during retrieval, with larger areas activated during retrieval. Subjects with mild cognitive impairment showed decreased magnitude of activation in bilateral frontal cortex regions (during encoding and retrieval), the left hippocampus (during retrieval), and the left cerebellum (during encoding) compared with magnitude of activation in control subjects (P < .001). Patients with mild cognitive impairment showed increased activation in the posterior frontal lobes (during retrieval) (P < .001). Lower hippocampal activation during retrieval was the most significant correlate of clinical severity of memory loss in mild cognitive impairment (P < .001). CONCLUSION: A difference exists in the response of brain regions underlying encoding and retrieval in mild cognitive impairment. Memory deficits in mild cognitive impairment may be linked to functional alterations in several specific brain regions both inside and outside the medial temporal lobe.

Aged↗
PubMed2006

Elevation in plasma Abeta42 in geriatric depression: a pilot study.

Elevated plasma amyloid beta 1-42 (Abeta42) level has been linked to increased risk for incident AD in cognitively-intact elderly. However, plasma Abeta levels in individuals with late-life depression (LLMD), especially those with a late age of onset of first depressive episode, who are at a particularly increased risk for Alzheimer's disease, have not been studied. We compared plasma Abeta in 47 elderly with LLMD with 35 controls and examined its relationships to age of onset of first depressive episode, antidepressant treatment (paroxetine or nortriptyline), and indices of platelet activation (platelet factor 4 and beta-thromboglobulin) and brain abnormalities. Results indicated that plasma Abeta42 levels and the Abeta42/40 ratio were elevated in the LLMD group relative to controls in the overall group analyses and in the age- and gender-matched groups. MRI data indicated that higher Abeta42/40 ratio was associated with greater severity of total white matter hyperintensity burden in LLMD. Plasma Abeta levels in LLMD were not influenced by age of onset of first depressive episode or antidepressant treatment and were not related to indices of platelet activation. Our preliminary results suggest that increased plasma Abeta42 and Abeta42/40 ratio are present in geriatric depression, and future studies should be done to confirm these findings and to determine their relationship to cognitive decline and brain abnormalities associated with LLMD.

Aged↗
PubMed2006

Accuracy of spatial normalization of the hippocampus: implications for fMRI research in memory disorders.

Functional magnetic resonance imaging (fMRI) studies in memory impairment have detected functional alterations in medial temporal lobe (MTL) structures, notably the hippocampus. Many of these studies employ spatial normalization to place subjects in a standardized template space prior to analysis; however, little is known about the effects of local atrophy on the normalization process in structures such as the hippocampus. The purpose of this study was to compare the accuracy of spatial normalization of the hippocampus between memory-impaired patients and controls. Twenty clinically-defined mild cognitive impairment (MCI) subjects and twenty elderly controls were studied at 4T with structural and functional MRI during a memory encoding-retrieval task. Bilateral hippocampal regions-of-interest (ROIs) were manually drawn for all subjects and further divided into anterior/posterior subregions. To assess normalization accuracy to the Montreal Neurological Institute template, the percentage of each template-defined hippocampal ROI originating from true hippocampal tissue was determined for all subjects. To assess the ability of spatial normalization to equalize group differences in hippocampal volume, pre- and post-normalization hippocampal volumes were compared. Finally, fMRI measures from template and non-template analyses were compared. Poorer normalization accuracy of the bilateral hippocampi, particularly the posterior portions, was found for MCI subjects. Significant group differences were found in left hippocampal and bilateral posterior hippocampal volumes, and these differences were not corrected with normalization. Hippocampal volumes were significantly correlated with normalization accuracy across MCI and control groups, but some significant differences in normalization accuracy persisted independent of these volume differences. Template and non-template fMRI analyses were significantly correlated in controls, but not MCI subjects, during memory retrieval. These findings suggest decreased normalization accuracy in memory-impaired subjects is a potentially important confounder of template-based fMRI analyses in the hippocampus and MTL.

Adult↗
PubMed2006

Cognitive function in late life depression: relationships to depression severity, cerebrovascular risk factors and processing speed.

BACKGROUND: A number of studies have examined clinical factors linked to worse neuropsychological performance in late life depression (LLD). To understand the influence of LLD on cognition, it is important to determine if deficits in a number of cognitive domains are relatively independent, or mediated by depression- related deficits in a basic domain such as processing speed. METHODS: Patients who met DSM-IV criteria for major depression (n = 155) were administered a comprehensive neuropsychological battery of tasks grouped into episodic memory, language, working memory, executive function, and processing speed domains. Multiple regression analyses were conducted to determine contributions of predictor variables to cognitive domains. RESULTS: Age, depression severity, education, race and vascular risk factors all made significant and independent contributions to one or more domains of cognitive function, with all five making independent contributions to processing speed. Age of onset made no independent contribution, after accounting for age and vascular risk factors. Of the five cognitive domains investigated, changes in processing speed were found to most fully mediate the influence of predictor variables on all other cognitive domains. CONCLUSIONS: While slowed processing speed appears to be the most core cognitive deficit in LLD, it was closely followed by executive function as a core cognitive deficit. Future research is needed to help clarify mechanisms leading to LLD- related changes in processing speed, including the potential role of white matter abnormalities.

Activities of Daily Living↗
PubMed2006

Safety and efficacy of rivastigmine in adolescents with Down syndrome: a preliminary 20-week, open-label study.

Individuals with Down syndrome (DS) exhibit a cholinergic deficiency similar to that found in Alzheimer's disease. Cholinesterase inhibitors, used to treat Alzheimer's disease, may improve cognitive function in individuals with DS. This is the first investigation of the safety and efficacy of rivastigmine (an acetyl and butyryl cholinesterase inhibitor) on specific cognitive domains in pediatric DS. Eleven subjects with DS (ages 10-17 years) were treated with a liquid formulation of rivastigmine. Four subjects experienced no adverse events (AEs). Seven subjects reported AEs that were mild, transient and consistent with adverse events typically noted with cholinesterase inhibitors. Significant improvements were found in overall adaptive function (Vineland Adaptive Behavior Scales and Clinician's Interview-Based Impression of Change), attention (Leiter Attention Sustained tests A and B), memory (NEPSY: Narrative and Immediate Memory for Names subtests) and language (Test of Verbal Expression and Reasoning and Clinical Evaluation of Language Fundamentals-Preschool) domains. Improved language performance was found across all functional levels. These results underscore the need for larger, controlled studies employing a carefully constructed test battery capable of measuring the full scope of performance across multiple domains and a wide range of functional levels.

Adaptation, Psychological↗
PubMed2006

Pharmacological strategies for the prevention of Alzheimer's disease.

This review examines key pharmacological strategies that have been clinically studied for the primary or secondary prevention of Alzheimer's disease. Much information (neuropsychological, genetic and imaging) is already available to characterise an individual's risk for developing Alzheimer's disease. However, regulatory pathways for obtaining a prevention indication are less well charted, and such trials tend to involve 3- to 7-year studies of 1000 - 5000 individuals, depending on baseline status. Treatments developed for prevention will also need to have superior safety. For these reasons, > 100 proprietary pharmacological products are currently being developed for an Alzheimer's disease treatment, but only a few are being studied for prevention. Randomised trial data are available for antihypertensive agents (calcium channel blockers, angiotensin-converting enzyme inhibitors), pravastatin, simvastatin, conjugated oestrogen, raloxifene, rofecoxib, CX516 (AMPA agonist) and cholinesterase inhibitors regarding efficacy for Alzheimer's disease prevention. At least four large prevention trials of conjugated oestrogen, selenium and vitamin E, Ginkgo biloba and statins are currently underway. Strategies using other agents have not yet been evaluated in Alzheimer's disease prevention clinical trials. These include anti-amyloid antibodies, active immunisation, selective secretase inhibitors and modulators, microtubule stabilisers (e.g., paclitaxel), R-flurbiprofen, xaliproden, ONO-2506, FK962 (somatostatin releaser), SGS 742 (GABA(B) antagonist), TCH 346 (apoptosis inhibitor), Alzhemedtrade mark, phophodiesterase inhibitors, rosiglitazone, leuprolide, interferons, metal-protein attenuating compounds (e.g., PBT2), CX717, rasagaline, huperzine A, antioxidants and memantine. Studies combining lifestyle modification and drug therapy have not been conducted. Full validation of surrogate markers for disease progression (such as amyloid imaging) should further facilitate drug development. Reducing the complexity of prevention trials and gaining regulatory consensus of design is a high priority for the field.

Alzheimer Disease↗
PubMed2006

Atypical antipsychotics and pituitary tumors: a pharmacovigilance study.

STUDY OBJECTIVE: To analyze the disproportionality of reporting of hyperprolactinemia, galactorrhea, and pituitary tumors with seven widely used antipsychotic drugs. DESIGN: Retrospective pharmacovigilance study. DATA SOURCE: United States Food and Drug Administration's Adverse Event Reporting System (AERS) database. INTERVENTION: We initially identified higher-than-expected postmarketing reports of pituitary tumors associated with risperidone, a potent dopamine D2-receptor antagonist antipsychotic, by analyzing reporting patterns of these tumors in the AERS database. To further examine this association, we analyzed disproportionate reporting patterns of pituitary tumor reports for seven antipsychotics with different affinities for blocking D2 receptors: aripiprazole, clozapine, olanzapine, quetiapine, risperidone, ziprasidone, and haloperidol. MEASUREMENTS AND MAIN RESULTS: To conduct both of these analyses, we used the Multi-item Gamma Poisson Shrinker (MGPS) data mining algorithm applied to the AERS database. The MGPS uses a Bayesian model to calculate adjusted observed:expected ratios of drug-adverse event associations (Empiric Bayes Geometric Mean [EBGM] values) in huge drug safety databases. The higher the adjusted reporting ratio, or EBGM value, the greater the strength of the association between a drug and an adverse event. Risperidone had the highest adjusted reporting ratios for hyperprolactinemia (EBGM 34.9, 90% confidence interval [CI] 32.8-37.1]), galactorrhea (EBGM 19.9, 90% CI 18.6-21.4), and pituitary tumor (EBGM 18.7, 90% CI 14.9-23.3) among the seven antipsychotics, and one of the highest scores for all drugs in the AERS database. Some tumors were associated with visual field defects, hemorrhage, convulsions, surgery, and severe (>10-fold) prolactin elevations. The EBGM values for risperidone for these adverse events were higher in women, but high EBGM values for these events were also seen in men and children. Moreover, the rank order of the EBGM values for pituitary tumors corresponded to the affinities of these seven drugs for D2 receptors. CONCLUSION: Treatment with potent D2-receptor antagonists, such as risperidone, may be associated with pituitary tumors. These findings are consistent with animal (mice) studies and raise the need for clinical awareness and longitudinal studies.

Adolescent↗
PubMed2006

A randomized controlled trial of paroxetine for noncardiac chest pain.

Noncardiac chest pain occurs frequently in medical practice and is often difficult to treat. We conducted a randomized double-blind, placebo-controlled, 8-week trial of paroxetine in 50 patients with noncardiac chest pain. None of the patients met criteria for panic disorder or major depression. Paroxetine-treated patients showed greater (P < .05) improvements than placebo-treated patients on the Clinical Global Impressions (CGI) scale. Both paroxetine and placebo-treated patients improved to a similar extent on selfrated pain measures, although baseline differences limited the interpretation of this outcome variable. There were no differences on other outcome ratings. Treatment was well tolerated. These preliminary findings extend other data on the potential of selective serotonin reuptake inhibitors for the acute treatment of noncardiac chest pain. Some recommendations for future studies to definitively test this potential are presented.

Adult↗
PubMed2005

Current status of functional MR imaging, perfusion-weighted imaging, and diffusion-tensor imaging in Alzheimer's disease diagnosis and research.

Advanced MR techniques, such as functional MR imaging, perfusion-weighted imaging, and diffusion-tensor imaging, offer the capability of detecting early functional, hemodynamic, and microstructural alterations in Alzheimer's disease before gross anatomic alterations. Most studies of these emerging technologies are at the exploratory stage, with the purpose of increasing understanding of the underlying disease process and defining cross-sectional differences across various subject populations. Assessment of the diagnostic efficacy of these technologies in detecting early Alzheimer's disease in its preclinical and prodromal stages is ongoing.

Aged↗
PubMed2005

A review of 1H MR spectroscopy findings in Alzheimer's disease.

Hydrogen-1 MR spectroscopy (MRS) studies demonstrate metabolic differences between patients who have Alzheimer's disease (AD) and cognitive normal age-matched controls. Clinical MRS also shows regional variations in metabolites between patients who have AD and those who have other dementias. Single-voxel and volumetric standard MRS techniques and automated data processing software are available for clinical MR scanners. Improvements in specificity and sensitivity of AD diagnosis, using MRS techniques as an adjunct to clinical imaging, are under evaluation. Multiparametric data analyses show, however, that metabolite changes correlate with in-vitro, postmortem, and metabolic changes and to changes in or predictions of cognitive scores.

Alzheimer Disease↗
PubMed2005

Statins and cognition: what can we learn from existing randomized trials?

BACKGROUND: Statins are being developed as treatments for Alzheimer's dementia based on evidence from preclinical and observational studies. However, cholesterol plays an integral role in cell membrane signal transduction and suboptimal cholesterol level could potentially impair neuronal function. Additionally, results of observational nonrandomized studies may have been affected by treatment bias. METHODS: We performed a systematic literature review in MEDLINE from January 1966 to July 2004 and included published prospective, randomized, and placebo-controlled human studies that examined the cognitive effects of statins. RESULTS: Nine studies with sample sizes ranging from 22 to 20,000 and duration of 3 weeks to 5 years, met criteria for review. Study populations and cognitive outcomes varied. Four studies were >6 months or longer. Overall, none of these studies reported finding a positive benefit for any statin on cognition in non-demented subjects although there was inconsistent evidence for acute cognitive worsening in some studies. CONCLUSION: While statins intuitively have appeal for the prevention or treatment of dementia, any conclusions about their efficacy should await more definitive evidence from on-going prospective clinical trials.

Alzheimer Disease↗
PubMed2005

Increasing memory load modulates regional brain activity in older adults as measured by fMRI.

Several recent studies using functional magnetic resonance imaging (fMRI) during recognition memory tests have suggested that the ability to neuromodulate as a function of cognitive demand may be impaired in older adults due to age-related cell loss and neural volume reduction in memory specific regions. In the current study, older adults (ages 59-77) were tested with fMRI during a delayed-recognition task in which memory load for faces was varied across trials. Activity was greater in amplitude for three- versus one-face stimuli within the superior, middle, and inferior frontal gyri, intraparietal sulcus, and fusiform gyrus. It was concluded that the ability to modulate activity with increasing load is preserved in older adults despite reductions in neural volume.

Aged↗