Papers by Prabha Siddarth
Molecular Psychiatry, May 7, 2020
Drugs that target glutamate neuronal transmission, such as memantine, offer a novel approach to t... more Drugs that target glutamate neuronal transmission, such as memantine, offer a novel approach to the treatment of late-life depression, which is frequently comorbid with cognitive impairment. The results of our recently published double-blind, randomized, placebo-controlled trial of escitalopram or escitalopram/memantine in late-life depression with subjective memory complaints ({"type":"clinical-trial","attrs":{"text":"NCT01902004","term_id":"NCT01902004"}}NCT01902004) indicated no differences between treatments in depression remission, but additional benefits in cognition at 12-month follow-up with combination treatment. To identify pathways and biological functions uniquely induced by combination treatment that may explain cognitive improvements, we generated transcriptional profiles of remission compared with non-remission from whole blood samples. Remitters to escitalopram compared with escitalopram/memantine combination treatment display unique patterns of gene expression at baseline and 6 months after treatment initiation. Functional enrichment analysis demonstrates that escitalopram-based remission associates to functions related to cellular proliferation, apoptosis, and inflammatory response. Escitalopram/memantine-based remission, however, is characterized by processes related to cellular clearance, metabolism, and cytoskeletal dynamics. Both treatments modulate inflammatory responses, albeit via different effector pathways. Additional research is needed to understand the implications of these results in explaining the observed superior effects of combination treatment on cognition observed with prolonged treatment.
The intestinal microbiota as a predictor for antidepressant treatment outcome in geriatric depression: a prospective pilot study
International Psychogeriatrics, Mar 24, 2021
ABSTRACTObjectives:(1) To investigate if gut microbiota can be a predictor of remission in geriat... more ABSTRACTObjectives:(1) To investigate if gut microbiota can be a predictor of remission in geriatric depression and to identify features of the gut microbiota that is associated with remission. (2) To determine if changes in gut microbiota occur with remission in geriatric depression.Design:Secondary analysis of a parent randomized placebo-controlled trial (NCT02466958).Setting:Los Angeles, CA, USA (2016-2018)Participants:Seventeen subjects with major depressive disorder, over 60 years of age, 41.2% female.Intervention:Levomilacipran (LVM) or placebo.Measurements:Remission was defined by Hamilton Depression Rating Scale score of 6 or less at 12 weeks. 16S-ribosomal RNA sequencing based fecal microbiota composition and diversity were measured at baseline and 12 weeks. Differences in fecal microbiota were evaluated between remitters and non-remitters as well as between baseline and post-treatment samples. LVM and placebo groups were combined in all the analyses.Results:Baseline microbiota showed no community level α-diversity or β-diversity differences between remitters and non-remitters. At the individual taxa level, a random forest classifier created with nine genera from the baseline microbiota was highly accurate in predicting remission (AUC = .857). Of these, baseline enrichment of Faecalibacterium, Agathobacter and Roseburia relative to a reference frame was associated with treatment outcome of remission. Differential abundance analysis revealed significant genus level changes from baseline to post-treatment in remitters, but not in non-remitters.Conclusions:This is the first study demonstrating fecal microbiota as a potential predictor of treatment response in geriatric depression. Our findings need to be confirmed in larger prospective studies.
Journal of Geriatric Psychiatry and Neurology, Apr 11, 2022
ObjectivesTwo-thirds of individuals living with Alzheimer’s disease are women. Declining estrogen... more ObjectivesTwo-thirds of individuals living with Alzheimer’s disease are women. Declining estrogen levels influence mood and cognition. Cumulative lifetime estrogen exposure (CLEE) correlates with cognition later in life. We examined the relationship of CLEE to depression and cognition in older women with major depression compared to non-depressed women.DesignOlder women (age ≥60 years) with depression were compared to non-depressed women using a lifetime estrogen exposure questionnaire. CLEE was defined as combined durations of reproductive span (age of menopause minus age of menarche) and any post-menopausal hormone replacement therapy use. Higher vs lower CLEE groups were based on a median of 474 months of estrogen exposure.SettingUniversity hospital outpatient research programParticipants135 women ≥60 years; 64 depressed and 71 non-depressedMeasurmentsParticipants completed a comprehensive cognitive test battery. General linear models were used to examine the association between cognitive domain scores and CLEE in depressed and non-depressed women, controlling for age, education, and ethnicity.ResultsDepressed and non-depressed groups had significantly different levels of CLEE, measured in months: mean 495.7 (SD 108.6) vs 456.4 (SD 66.0) months, F(1,130) = 5.01, p = .03. Within the non-depressed participants, higher CLEE was associated with improved delayed recall (F(1,59) = 5.94, p = .02, effect size = .61), while no such relationship was observed in the depressed group.ConclusionHigher CLEE was associated with improvement in delayed recall among non-depressed, but not among depressed participants. This suggests a protective role of estrogen on memory in non-depressed older postmenopausal women. Further research should examine the role of the CLEE in antidepressant response and cognitive decline.
Cannabis and cannabinoid research, Dec 1, 2018
Background and Aims: Legalization of cannabis (CB) for both medicinal and, in some states, recrea... more Background and Aims: Legalization of cannabis (CB) for both medicinal and, in some states, recreational use, has given rise to increasing usage rates across the country. Of particular concern are indications that frequent CB use may be selectively harmful to the developing adolescent brain compared with adult-onset usage. However, the long-term effects of heavy, adolescent CB use on brain structure and cognitive performance in late-life remain unknown. A critical brain region is the hippocampus (HC), where there is a striking intersection between high concentrations of cannabinoid 1 (CB1) receptors and age-related pathology. Design: We investigated whether older adults (average age = 66.6 + 7.2 years old) with a history of early life CB use show morphological differences in hippocampal subregions compared with older, nonusers. Methods: We performed high-resolution magnetic resonance imaging combined with computational techniques to assess cortical thickness of the medial temporal lobe, neuropsychological testing, and extensive drug use histories on 50 subjects (24 formerly heavy cannabis users [CB+ group] abstinent for an average of 28.7 years, 26 nonusers [CBÀ group]). We investigated group differences in hippocampal subregions, controlling for age, sex, and intelligence (as measured by the Wechsler Test of Adult Reading), years of education, and cigarette use. Results: The CB+ subjects exhibited thinner cortices in subfields cornu ammonis 1 [CA1; F(1,42) = 9.96, p = 0.0003], and CA2, 3, and the dentate gyrus [CA23DG; F(1,42) = 23.17, p < 0.0001], and in the entire HC averaged over all subregions [F(1,42) = 8.49, p = 0.006]. Conclusions: Negative effects of chronic adolescent CB use on hippocampal structure are maintained well into late life. Because hippocampal cortical loss underlies and exacerbates age-related cognitive decline, these findings have profound implications for aging adults with a history of early life usage. Clinical Trial Registration: ClinicalTrials.gov # NCT01874886.
American Journal of Geriatric Psychiatry, Feb 1, 2020
Objectives-Geriatric depression is difficult to treat and frequently accompanied by cognitive com... more Objectives-Geriatric depression is difficult to treat and frequently accompanied by cognitive complaints that increase risk for dementia. New treatment strategies targeting both depression and cognition are urgently needed. Methods-We conducted a 6-month double-blind placebo-controlled trial to assess the efficacy and tolerability of escitalopram + memantine (ESC/MEM) compared to escitalopram + placebo (ESC/PBO) for improving mood and cognitive functioning in depressed older adults with subjective memory complaints (). Primary outcome was change in depression as assessed by the HAM-D post-treatment (at 6 months). Remission was defined as HAM-D <6; naturalistic followup continued until 12 months. Results-Of the 95 randomized participants, 62 completed the 6-month assessment. Dropout and tolerability did not differ between groups. Mean daily escitalopram dose was 11.1 mg (SD=3.7; range: 5-20 mg). Mean daily memantine dose was 19.3 mg (SD=2.6; range 10-20 mg). Remission rate within ESC/MEM was 45.8% and 47.9%, compared to 38.3% and 31.9% in ESC/PBO, at 3 and 6 months respectively (χ 2 (1)=2.0, p=0.15). Both groups improved significantly on the HAM-D at 3, 6 and 12 months, with no observed between-group differences. ESC/MEM demonstrated greater improvement in delayed recall (F(2,82)=4.3, p=.02) and executive functioning (F(2,82)=5.1, p=.01) at 12 months compared to ESC/PBO. Conclusions-The combination of memantine with escitalopram was well-tolerated and as effective as escitalopram and placebo in improving depression using HAM-D. Combination
165. Impact of Yoga Training on Hippocampal Connectivity in Older Women at Risk for Alzheimer’s Disease
Biological Psychiatry, May 1, 2023
Effects of Electronic Cigarette Exposure on Myocardial Infarction and No-Reflow, and Cardiac Function in a Rat Model
Journal of Cardiovascular Pharmacology and Therapeutics, 2023
Purpose: We investigated the effects of exposure to electronic cigarettes (E-cig) vapor on the si... more Purpose: We investigated the effects of exposure to electronic cigarettes (E-cig) vapor on the sizes of the no-reflow and myocardial infarction regions, and cardiovascular function compared to exposure to purified air and standard cigarette smoke. Methods and Results: Sprague Dawley rats (both male and female, 6 weeks old) were successfully exposed to filtered air (n = 32), E-cig with nicotine (E-cig Nic+, n = 26), E-cig without nicotine (E-cig Nic−, n = 26), or standard cigarette smoke (1R6F reference, n = 31). All rats were exposed to inhalation exposure for 8 weeks, prior to being subjected to 30 minutes of left coronary artery occlusion followed by 3 hours of reperfusion. Exposure to E-cig vapor with or without nicotine or exposure to standard cigarettes did not increase myocardial infarct size or worsen the no-reflow phenomenon. Exposure to E-cig Nic+ reduced the body weight gain, and increased the LV weight normalized to body weight and LV wall thickness and enhanced the collagen deposition within the LV wall. E-cig exposure led to cardiovascular dysfunction, such as reductions in cardiac output, LV positive and negative dp/dt, suggesting a reduction in contractility and relaxation, and increased systemic arterial resistance after coronary artery occlusion and reperfusion in rats compared to air or cigarette exposure. Conclusions: E-cig exposure did not increase myocardial infarct size or worsen the no-reflow phenomenon, but induced deleterious changes in LV structure leading to cardiovascular dysfunction and increased systemic arterial resistance after coronary artery occlusion followed by reperfusion.
Yoga training's effects on inflammatory markers and cognitive function in women at high risk for Alzheimer's Disease
American Journal of Geriatric Psychiatry, Mar 1, 2023
medRxiv (Cold Spring Harbor Laboratory), May 29, 2022
Due to their genetic instability, tumor cells bear mutations that can effectively be recognized b... more Due to their genetic instability, tumor cells bear mutations that can effectively be recognized by the immune system. In the clinic, immune checkpoint immunotherapy (ICI) can reactivate immune reactions against mutated proteins, known as neoantigens, leading to remarkable remission in cancer patients. Nevertheless, only a minority of patients are responsive to ICI, and approaches for prediction of responsiveness remain elusive yet are needed to improve the success of cancer treatments. While the tumor mutational burden (TMB) correlates positively with responsiveness and survival of patients undergoing ICI therapy, the influence of the subcellular localizations of the mutated proteins within the tumor cell has not been elucidated. Here, we hypothesized that the immune reactions are modulated by the localization of the mutated proteins and, therefore, that some subcellular localizations could favor responsiveness to ICI. We show in both a mouse melanoma model and human clinical datasets of 1722 ICI-treated patients that high membranelocalized tumor mutational burden (mTMB), particularly at the plasma membrane, correlate with responsiveness to ICI therapy and improved overall survival across multiple cancer types. We further highlight that mutations in the genes encoding for the membrane proteins NOTCH3, RNF43, NTRK3 and NOTCH1, among others, may serve as potent biomarkers to predict extended survival upon ICI in certain cancer types. We anticipate that our results will improve the predictability of cancer patient response to ICI and therefore may have important implications to establish future clinical guidelines to direct the choice of treatment toward ICI.
Brain, Behavior, & Immunity - Health, Dec 1, 2020
Lymphangiogenesis is a potential indicator of cancer patients' survival. However, there is no sta... more Lymphangiogenesis is a potential indicator of cancer patients' survival. However, there is no standardisation of methodologies applied to the assessment of lymphatic vessel density. In 156 invasive ductal breast cancers (T ≥ 1/N+/M0), lymphatic and blood vessels were visualised using podoplanin and CD34, respectively. Based on these markers expression, four parameters were assessed: (i) distribution of podoplanin-stained vessels (DPV)-the percentage of fields with at least one lymphatic vessel (a simple method proposed by us), (ii) lymphatic vessel density (LVD), (iii) LVD to microvessel density ratio (LVD/MVD) and (iv) the expression of podoplanin in cancer-associated fibroblasts. Next, we estimated relations between the above-mentioned parameters and: (i) breast cancer subtype, (ii) tumour grade, and (iii) basal markers expression. We found that intensive lymphangiogenesis, assessed using all studied methods, is positively related to high tumour grade, triple negative or HER2 subtype and expression of basal markers. Whereas, the absence of podoplanin expression in fibroblasts of cancer stroma is related to luminal A subtype, low tumour grade or lack of basal markers expression. Distribution of podoplanin-stained vessels, assessed by a simple method proposed by us (indicating the percentage of fields with at least one lymphatic vessel), might be used instead of the "hot-spot" method.
Neuropsychopharmacology, Dec 1, 2013
Introduction: Previous research has identified modifiable risk factors for Alzheimer's disease (A... more Introduction: Previous research has identified modifiable risk factors for Alzheimer's disease (AD) in older adults. Research is limited on the potential link between these risk factors and subjective memory impairment (SMI), which may precede AD and other dementias. Examination of these potential relationships may help identify those at risk for AD at a stage when interventions may delay or prevent further memory problems. The objective of this study was to determine whether risk factors for AD are associated with SMI among different age groups. Method: Trained interviewers conducted daily telephone surveys (Gallup-Healthways) of a representative community sample of 18,614 U.S. respondents, including 4,425 younger (age 18 to 39 years), 6,365 middle-aged (40 to 59 years), and 7,824 older (60 to 99 years) adults. The surveyors collected data on demographics, lifestyles, and medical information. Less education, smoking, hypertension, diabetes, less exercise, obesity and depression, and interactions among them, were examined for associations with SMI. Weighted logistic regressions and chi-square tests were used to calculate odds ratios and confidence intervals for SMI with each risk factor and pairwise interactions across age groups. Results: Depression, less education, less exercise, and hypertension were significantly associated with SMI in all three age groups. Several interactions between risk factors were significant in younger and middle-aged adults and influenced their associations with SMI. Frequency of SMI increased with age and number of risk factors. Odds of having SMI increased significantly with just having one risk factor. Conclusions: These results indicate that modifiable risk factors for AD are also associated with SMI, suggesting that these relationships occur in a broad range of ages and may be targeted to mitigate further memory problems. Whether modifying these risk factors reduces SMI and the eventual incidence of AD and other dementias later in life remains to be determined.
Journal of Alzheimer's Disease, May 17, 2022
Background: Female sex, subjective cognitive decline (SCD), and cardiovascular risk factors (CVRF... more Background: Female sex, subjective cognitive decline (SCD), and cardiovascular risk factors (CVRFs) are known risk factors for developing Alzheimer's disease (AD). We previously demonstrated that yoga improved depression, resilience, memory and executive functions, increased hippocampal choline concentrations, and modulated brain connectivity in older adults with mild cognitive impairment. Objective: In this study (NCT03503669), we investigated brain gray matter volume (GMV) changes in older women with SCD and CVRFs following three months of yoga compared to memory enhancement training (MET). Methods: Eleven women (mean age = 61.45, SD = 6.58) with CVRF and SCD completed twelve weeks of Kundalini Yoga and Kirtan Kriya (KY + KK) while eleven women (mean age = 64.55, SD = 6.41) underwent MET. Anxiety, resilience, stress, and depression were assessed at baseline and 12 weeks, as were T1-weighted MRI scans (Siemens 3T Prisma scanner). We used Freesurfer 6.0 and tested group differences in GMV change, applying Monte-Carlo simulations with alpha = 0.05. Region-of-interest analysis was performed for hippocampus and amygdala. Results: Compared to KY + KK, MET showed reductions in GMV in left prefrontal, pre-and post-central, supramarginal, superior temporal and pericalcarine cortices, right paracentral, postcentral, superior and inferior parietal cortices, the banks of the superior temporal sulcus, and the pars opercularis. Right hippocampal volume increased after yoga but did not survive corrections. Conclusion: Yoga training may offer neuroprotective effects compared to MET in preventing neurodegenerative changes and cognitive decline, even over short time intervals. Future analyses will address changes in functional connectivity in both groups.
Mental Health & Prevention, Dec 1, 2018
Objective: While behavioral risk factors for depression have been assessed in select samples, pre... more Objective: While behavioral risk factors for depression have been assessed in select samples, previous research is limited in addressing such correlates across the lifespan. To this end, we assessed the relationship between self-reported depression and four behavioral risk factors (smoking, obesity, limited physical activity, and less healthy diet) in a representative United States adult sample. Methods: Data were drawn from 30,116 Gallup-Healthways survey respondents, and stratified according to younger (18-39), middle-aged (40-59), and older (60-99) adults. The survey included demographic information, questions relating to the four risk factors, and an item on self-reported depression. Weighted multivariable logistic regressions, controlling for sex, ethnicity, and socioeconomic variables, were used to calculate odds ratios (OR) and confidence intervals (CI) for each correlate. Results: Sixteen percent of respondents endorsed a prior diagnosis of depression; 17% smoked; 26% were obese; 50% engaged in limited physical activity; and 41% had a less healthy diet. Smoking was most strongly associated with risk for depression (OR: 2.71, 95% CI [2.41-3.04], 1.81 [1.62-2.02] and 1.82 [1.55-2.15] for younger, middle-aged and older age groups, respectively), followed by obesity (
American Journal of Geriatric Psychiatry, Jul 1, 2012
Objectives-Identification of risk factors for Alzheimer disease (AD) is critical for establishing... more Objectives-Identification of risk factors for Alzheimer disease (AD) is critical for establishing effective diagnostic and therapeutic strategies. Carrying the 4 allele of the apolipoprotein E gene (APOE4) and having a family history of the disease are two such factors, with family history risk reflecting additional yet unknown or rarely studied genetic and perhaps nongenetic risks. Our aim was to determine the influence of APOE genotype and family history status on cognitive performance in healthy individuals. Design-Longitudinal study.
International Psychogeriatrics, Jun 29, 2023
Objectives: Geriatric depression (GD) is associated with significant medical comorbidity, cogniti... more Objectives: Geriatric depression (GD) is associated with significant medical comorbidity, cognitive impairment, brain atrophy, premature mortality, and suboptimal treatment response. While apathy and anxiety are common comorbidities, resilience is a protective factor. Understanding the relationships between brain morphometry, depression, and resilience in GD could inform clinical treatment. Only few studies have addressed gray matter volume (GMV) associations with mood and resilience. Participants: Forty-nine adults aged >60 years (38 women) with major depressive disorder undergoing concurrent antidepressant treatment participated in the study. Measurements: Anatomical T1-weighted scans, apathy, anxiety, and resilience data were collected. Freesurfer 6.0 was used to preprocess T1-weighted images and qdec to perform voxel-wise whole-brain analyses. Partial Spearman correlations controlling for age and sex tested the associations between clinical scores, and general linear models identified clusters of associations between GMV and clinical scores, with age and sex as covariates. Cluster correction and Monte-Carlo simulations were applied (corrected alpha = 0.05). Results: Greater depression severity was associated with greater anxiety (r = 0.53, p = 0.0001), lower resilience (r = − 0.33, p = 0.03), and greater apathy (r = 0.39, p = 0.01). Greater GMV in widespread, partially overlapping clusters across the brain was associated with reduced anxiety and apathy, as well as increased resilience. Conclusion: Our results suggest that greater GMV in extended brain regions is a potential marker for resilience in GD, while GMV in more focal and overlapping regions may be markers for depression and anxiety. Interventions focused on improving symptoms in GD may seek to examine their effects on these brain regions.
Nonmemory-Related Neuropsychological Markers of Alzheimer's Disease
PsycEXTRA Dataset, 2006
Default mode network connectivity and treatment response in geriatric depression
Brain and behavior, Mar 1, 2022
ObjectivesDefault mode network (DMN) connectivity is altered in depression. We evaluated the rela... more ObjectivesDefault mode network (DMN) connectivity is altered in depression. We evaluated the relationship between changes in within‐network DMN connectivity and improvement in depression in a subsample of our parent clinical trial comparing escitalopram/memantine (ESC/MEM) to escitalopram/placebo (ESC/PBO) in older depressed adults (NCT01902004).MethodsTwenty‐six participants with major depression (age &gt; 60 years) and subjective memory complaints underwent treatment with ESC/MEM (n = 13) or ESC/PBO (n = 13), and completed baseline and 3‐month follow‐up resting state magnetic resonance imaging scans. Multi‐block partial least squares correlation analysis was used to evaluate the impact of treatment on within‐network DMN connectivity changes and their relationship with symptom improvement at 3 months (controlling for age and sex).ResultsA significant latent variable was identified, reflecting within‐network DMN connectivity changes correlated with symptom improvement (p = .01). Specifically, although overall group differences in within‐network DMN connectivity changes failed to reach significance, increased within‐network connectivity of posterior/lateral DMN regions (precuneus, angular gyrus, superior/middle temporal cortex) was more strongly and positively correlated with symptom improvement in the ESC/MEM group (r = 0.97, 95% confidence interval: 0.86–0.98) than in the ESC/PBO group (r = 0.36, 95% confidence interval: 0.13–0.72).ConclusionsIncreased within‐network connectivity of core DMN nodes was more strongly correlated with depressive symptom improvement with ESC/MEM than with ESC/PBO, supporting an improved engagement of brain circuitry implicated in the amelioration of depressive symptoms with combined ESC/MEM treatment in older adults with depression and subjective memory complaints.
Promoting brain health in a digital world
Elsevier eBooks, 2024
Author response for "Default mode network connectivity and treatment response in geriatric depression
Annals of clinical and translational neurology, Jun 29, 2022
Estrogens have neuroprotective actions depending on estrogen type, dose, and timing in both precl... more Estrogens have neuroprotective actions depending on estrogen type, dose, and timing in both preclinical models and in women during health and disease. Serum neurofilament light chain is a putative biomarker of neurodegeneration in multiple sclerosis, aging, and other neurodegenerative diseases. Here, oral treatment with an estrogen unique to pregnancy (estriol) using an 8 mg dose to induce a mid‐pregnancy blood estriol level reduced serum neurofilament light chain in nonpregnant MS women at mean age of 37 years. This is consistent with estriol‐mediated protection from neuro‐axonal injury and supports the use of serum neurofilament light chain as a biomarker in MS.
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Papers by Prabha Siddarth