Papers by PRABHA SIDDARTH
Proceedings of the …
The major known genetic risk for Alzheimer's disease (AD), apolipoprotein E-4 (APOE-4), is a... more The major known genetic risk for Alzheimer's disease (AD), apolipoprotein E-4 (APOE-4), is associated with lowered parietal, temporal, and posterior cingulate cerebral glucose metabolism in patients with a clinical diagnosis of AD. To determine cognitive and metabolic decline patterns ...
Across species structural and functional hemispheric asymmetry is a fundamental feature of the br... more Across species structural and functional hemispheric asymmetry is a fundamental feature of the brain. Environmental and genetic factors determine this asymmetry during brain development and modulate its interaction with brain disorders. The e4 allele of the apolipoprotein E gene (APOE-4) is a risk factor for Alzheimer's disease, associated with regionally specific effects on brain morphology and function during the life span. Furthermore, entorhinal and hippocampal hemispheric asymmetry could be modified by pathology during Alzheimer's disease development. Using high-resolution magnetic resonance imaging and a cortical unfolding technique we investigated whether carrying the APOE-4 allele influences hemispheric asymmetry in the entorhinal cortex and the hippocampus among patients with Alzheimer's disease as well as in middle-aged and older cognitively healthy individuals. APOE-4 carriers showed a thinner entorhinal cortex in the left hemisphere when compared with the right hemisphere across all participants. Non-carriers of the allele showed this asymmetry only in the patient group. Cortical thickness in the hippocampus did not vary between hemispheres among APOE-4 allele carriers and noncarriers. The APOE-4 allele modulates hemispheric asymmetry in entorhinal cortical thickness. Among Alzheimer's disease patients, this asymmetry might be less dependent on the APOE genotype and a more general marker of incipient disease pathology.
Journal of pediatric psychology, Jan 9, 2018
Pediatric psychogenic nonepileptic seizures (PNES) is a functional somatic symptom condition with... more Pediatric psychogenic nonepileptic seizures (PNES) is a functional somatic symptom condition with significant health-care service burden. While both family and individual factors play an important role in the development and maintenance of PNES, little is known about what predicts urgent health-care use in families with children who have PNES. The aim of the current study was to explore whether child coping and parental bonding styles influence the decision to seek urgent medical care in these families. Data were analyzed from youth of age 8-18 years, 47 with PNES, and their 25 sibling controls. Parents provided the number of youth emergency room visits and hospitalizations in the preceding year. Youth completed a questionnaire about their coping styles and a measure about their mothers' and fathers' bonding styles. Using a mixed model with family as a random effect, we regressed urgent health-care use on participant type (youth with PNES or sibling), parental bonding style,...
Journal of Alzheimer's disease : JAD, Jan 17, 2018
Our group has shown that in vivo tau brain binding patterns from FDDNP-PET scans in retired profe... more Our group has shown that in vivo tau brain binding patterns from FDDNP-PET scans in retired professional football players with suspected chronic traumatic encephalopathy differ from those of tau and amyloid aggregate binding observed in Alzheimer's disease (AD) patients and cognitively-intact controls. To compare these findings with those from military personnel with histories of mild traumatic brain injury(mTBI). FDDNP-PET brain scans were compared among 7 military personnel and 15 retired players with mTBI histories and cognitive and/or mood symptoms, 24 AD patients, and 28 cognitively-intact controls. Nonparametric ANCOVAs with Tukey-Kramer adjusted post-hoc comparisons were used to test for significant differences in regional FDDNP binding among subject groups. FDDNP brain binding was higher in military personnel compared to controls in the amygdala, midbrain, medial thalamus, pons, frontal and anterior and posterior cingulate regions (p < 0.01-0.0001). Binding patterns i...
Journal of Alzheimer's disease : JAD, 2018
Several modifiable lifestyle factors have been shown to have potential beneficial effects in slow... more Several modifiable lifestyle factors have been shown to have potential beneficial effects in slowing cognitive decline. Two such factors that may affect cognitive performance and slow the progression of memory loss into dementia in older adults are cognitive training and physical activity. There are currently no effective treatments for dementia; therefore, preventative strategies to delay or prevent the onset of dementia are of critical importance. The aim of this study was to determine the relative effectiveness of simultaneous performance of memory training and aerobic exercise to a sequential performance intervention on memory functioning in older adults. 55 older adults (aged 60- 75) with subjective memory impairments (non-demented and non-MCI) completed the intervention that consisted of 90-minute small group classes held twice weekly. Participants were randomized to either 4-weeks of supervised strategy-based memory training done simultaneously while stationary cycling (SIM) ...
The American journal of geriatric psychiatry : official journal of the American Association for Geriatric Psychiatry, Jan 29, 2018
Considerable disagreement exists on the necessity and extent of adjustment for multiple compariso... more Considerable disagreement exists on the necessity and extent of adjustment for multiple comparisons. 1 Although many articles have discussed when and how to control for inflation of Type I errors (i.e., finding a difference between groups when none exists), there is no consensus in the literature regarding this issue. 2-4 It has been pointed out, however, that adjustment is not required when the research is addressing novel or exploratory hypotheses-that is, when one also needs to consider the risk of making a Type II error (i.e., finding no difference when one exists). 2,5 Adjusting only for Type I error increases the risk for Type II error. 6 Schulz and Grimes 7 recommend restricting the number of primary end points tested and confining significance testing to only those hypotheses specified beforehand. If
Epilepsia, 2018
Greenland et al and quantified the proportion of patients who were concomitantly exposed to other... more Greenland et al and quantified the proportion of patients who were concomitantly exposed to other high-risk drugs. Furthermore, we conducted exact logistic regression whenever a zero cell was observed to avoid sparse data bias. 2 In conclusion, we agree that data augmentation is a valid new method to avoid sparse data bias, but we do not necessarily agree that this method should have been used in our study. DISCLOSURE None of the authors have any conflict of interest to declare. We confirm that we have read the Journal's position on issues involved in ethical publication and affirm that this report is consistent with those guidelines.
International psychogeriatrics, Jan 16, 2018
Traditional perspectives conceptualize resilience as a trait and depression as resulting from res... more Traditional perspectives conceptualize resilience as a trait and depression as resulting from resilience deficiency. However, research indicates that resilience varies substantially even among adults who are clinically depressed, as well as across the lifespan of an individual. Few studies have investigated resilience in depression, and even fewer have examined resilience in depressed older adults. Three hundred thirty-seven adults ≥60 years with major depressive disorder completed the Connor-Davidson Resilience Scale (CD-RISC) and measures of mental health, quality of life (QOL), and medical comorbidity. Exploratory factor analysis was used to explore the factor structure of the CD-RISC. Correlations and general linear models were used to examine associations between resilience and other variables. The rotated component matrix indicated a four-factor model. Sorting of items by highest factor loading revealed constructs associated with (1) grit, (2) active coping self-efficacy, (3) ...
Journal of Alzheimer's disease : JAD, 2018
Physical activity (PA) plays a major role in maintaining cognition in older adults. PA has been s... more Physical activity (PA) plays a major role in maintaining cognition in older adults. PA has been shown to be correlated with total hippocampal volume, a memory-critical region within the medial temporal lobe (MTL). However, research on associations between PA and MTL sub-region integrity is limited. To examine the relationship between PA, MTL thickness, and its sub-regions, and cognitive function in non-demented older adults with memory complaints. Twenty-nine subjects aged ≥60 years, with memory complaints were recruited for this cross-sectional study. PA was tracked for 7 days using accelerometers, and average number of steps/day determined. Subjects were categorized into two groups: those who walked ≤4000 steps/day (lower PA) and those with >4000 steps/day (higher PA). Subjects received neuropsychological testing and 3T MRI scans. Nonparametric ANCOVAs controlling for age examined differences between the two groups. Twenty-six subjects aged 72.7(8.1) years completed the study. ...
The American journal of geriatric psychiatry : official journal of the American Association for Geriatric Psychiatry, Jan 27, 2017
Because curcumin's anti-inflammatory properties may protect the brain from neurodegeneration,... more Because curcumin's anti-inflammatory properties may protect the brain from neurodegeneration, we studied its effect on memory in non-demented adults and explored its impact on brain amyloid and tau accumulation using 2-(1-{6-[(2-[F-18]fluoroethyl)(methyl)amino]-2-naphthyl}ethylidene)malononitrile positron emission tomography (FDDNP-PET). Forty subjects (age 51-84 years) were randomized to a bioavailable form of curcumin (Theracurmin® 90 mg twice daily [N = 21]) or placebo (N = 19) for 18 months. Primary outcomes were verbal (Buschke Selective Reminding Test [SRT]) and visual (Brief Visual Memory Test-Revised [BVMT-R]) memory, and attention (Trail Making A) was a secondary outcome. FDDNP-PET signals (15 curcumin, 15 placebo) were determined in amygdala, hypothalamus, medial and lateral temporal, posterior cingulate, parietal, frontal, and motor (reference) regions. Mixed effects general linear models controlling for age and education, and effect sizes (ES; Cohen's d) were est...
The American Journal of Geriatric Psychiatry
Cognitive impairment associated with late-life depression can persist after remission of mood sym... more Cognitive impairment associated with late-life depression can persist after remission of mood symptoms. Apathy, a common symptom of late-life depression, often leads to worse clinical outcomes. We examined if severity of apathy mediates cognitive difficulties in a cohort of older adults with major depression. One hundred thirty-eight older adults with depression (54.4% female; mean [SD] age: 69.7 [7.4] years; mean [SD] education:15.6 [2.7] years) were recruited to participate in a treatment study, and only baseline data were analyzed. All participants received a comprehensive evaluation of depression, apathy, and cognition. We examined whether apathy mediated the relationship between depression and cognition, focusing our attention on memory and cognitive control. We then explored whether the mediation effects differed across women and men. Increased apathy was significantly associated with worse depression and lower performance in the cognitive control domain but not in memory. Higher depressive scores were significantly associated with worse cognitive control but not memory. Mediation analyses revealed a significant indirect effect on cognitive control by depression through increased apathy scores with the mediator accounting for 21% of the total effect. Stratifying by sex, we found that women exhibited a significant indirect effect, with the mediator accounting for 47% of the total effect, whereas there was no mediation by apathy in men. The findings imply that increased apathy mediates the relationship between cognition and depression. The identification of mediating effects may inform future treatment strategies and preventive interventions that can focus on decreasing apathy to improve cognition in late-life depression.
The American Journal of Geriatric Psychiatry
Objective: Growing evidence supports an association between increased blood pressure and: (a) poo... more Objective: Growing evidence supports an association between increased blood pressure and: (a) poor cognitive performance in older adults, and (b) various biomarkers of increased Alzheimer's disease (AD) neuropathology.The objective of this study was to determine whether systolic blood pressure (SBP) and diastolic blood pressure (DBP) were significantly associated with cognitive functioning in non-demented adults, and to examine in vivo AD pathology as a possible mediator of this association. Methods: Positron emission tomography (PET) scans with 2-(1-{6-[(2-[F-18]fluoroethyl)(methyl) amino]-2-naphthyl}ethylidene)malononitrile (FDDNP) provide in vivo measurements of plaque and tangle burden.A total of 101 non-demented older subjects with blood pressure data and FDDNP-PET scans were drawn from a larger study of predictors of cognitive decline. A neuropsychological test battery was used to compute "global cognitive scores" (averaged across five key domains), which served as an index of general cognitive functioning. Results: Higher DBP (but not SBP) was significantly associated with lower cognitive scores, controlling for age, sex, antihypertensive medication use, and ApoE genotype (η 2 = 0.06). However, this relationship was no longer significant after introducing FDDNP-PET binding as an additional covariate in the statistical models. In vivo plaque and tangle burden accounted for over 30% of the observed association between higher DBP and poorer cognitive performance. Conclusions: By suggesting a mediation of the relationship between DBP and cognitive functioning by FDDNP-PET binding, this study advances our understanding of some potential predictors of cognitive decline in non-demented adults, and underscores the importance of devising early multimodal interventions to more effectively combat degenerative brain disorders.
Pharmacopsychiatry, Jan 25, 2017
Vilazodone is a novel antidepressant agent that combines selective serotonin (5-HT) reuptake inhi... more Vilazodone is a novel antidepressant agent that combines selective serotonin (5-HT) reuptake inhibitor (SSRI) activity and 5-HT(1A) receptor partial agonist activity. A pilot study was conducted to compare vilazodone (novel compound) and paroxetine (gold standard) on antidepressant effects, tolerability, and inflammation and immune modulation. A 12-week, double-blind, randomized clinical trial was conducted with 56 nondemented older adults diagnosed with major depressive disorder (MDD). Between-group differences in mood, tolerability, and safety, as well as genomic markers of inflammation and immune modulation, were examined. Both treatment groups demonstrated similar improvement in depressed mood. Leukocyte gene expression profiles demonstrated reduction of specific proinflammatory gene transcripts and bioinformatic indications of reduced nuclear factor kappa B (NF-κB), activator protein (AP)-1, and cAMP response element binding (CREB) activity in the vilazodone group compared to t...
Epilepsy & behavior : E&B, May 17, 2017
This study examined the risk factors for learning problems (LP) in pediatric psychogenic non-epil... more This study examined the risk factors for learning problems (LP) in pediatric psychogenic non-epileptic seizures (PNES) and their specificity by comparing psychopathology, medical, cognitive/linguistic/achievement, bullying history, and parent education variables between subjects with PNES with and without LP and between subjects with PNES and siblings with LP. 55 subjects with PNES and 35 siblings, aged 8-18years, underwent cognitive, linguistic, and achievement testing, and completed somatization and anxiety sensitivity questionnaires. A semi-structured psychiatric interview about the child was administered to each subject and parent. Child self-report and/or parent report provided information on the presence/absence of LP. Parents also provided each subject's medical, psychiatric, family, and bullying history information. Sixty percent (33/55) of the PNES and 49% (17/35) of the sibling subjects had LP. A multivariable logistic regression demonstrated that bullying and impaired...
Epilepsia, 2016
Objective: This study identified items on the Child Behavior Checklist (CBCL) that predict those ... more Objective: This study identified items on the Child Behavior Checklist (CBCL) that predict those children and adolescents with epilepsy at highest risk for multiple psychiatric diagnoses. Methods: Three hundred twenty-eight children, ages 5-18 years, and their parents participated in separate structured psychiatric interviews about the children, which yielded Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition Text Revision (DSM-IV-TR) diagnoses. Parents completed the CBCL. The sample was divided into a younger (≤12 years, n = 214) group and an older (>12-18 years, n = 114) group. This study identified a reduced set of parent-reported CBCL items associated with Multiple Diagnoses versus Single Diagnosis versus No Diagnosis using chi-square tests and stepwise logistic regression. We then performed a generalized logistic regression with Multiple Diagnoses versus Single Diagnosis versus No Diagnosis as the dependent variable and the reduced CBCL set of items as predictors. We calculated the area under the ROC (receiver operating characteristic) curve (AUC) as a measure of diagnostic accuracy for pairwise comparisons. Results: For the younger group, seven items (clingy, cruelty/bullying, perfectionist, nervous, poor school work, inattentive, and sulks) had high diagnostic accuracy (AUC = 0.88), and for the older group, three items (disobedient at school, loner, and lies/cheats) had high accuracy (AUC = 0.91) when comparing children with multiple psychiatric diagnoses to children with no diagnosis. For both age groups, there was less diagnostic accuracy in identifying children with a single versus no diagnosis (AUC = 0.75 [young]; 0.70 [older]). Significance: These findings suggest that responses to these two subsets of parentreported CBCL items should alert clinicians to children and adolescents with epilepsy at risk for multiple psychiatric diagnoses and in need of a psychiatric referral.
Frontiers in Aging Neuroscience, 2016
Behavioral interventions are becoming increasingly popular approaches to ameliorate age-related c... more Behavioral interventions are becoming increasingly popular approaches to ameliorate age-related cognitive decline, but their underlying neurobiological mechanisms and clinical efficiency have not been fully elucidated. The present study explored brain plasticity associated with two behavioral interventions, memory enhancement training (MET) and a mind-body practice (yogic meditation), in healthy seniors with mild cognitive impairment (MCI) using structural magnetic resonance imaging (s-MRI) and proton magnetic resonance spectroscopy (1 H-MRS). Senior participants (age ≥55 years) with MCI were randomized to the MET or yogic meditation interventions. For both interventions, participants completed either MET training or Kundalini Yoga (KY) for 60-min sessions over 12 weeks, with 12-min daily homework assignments. Gray matter volume and metabolite concentrations in the dorsal anterior cingulate cortex (dACC) and bilateral hippocampus were measured by structural MRI and 1 H-MRS at baseline and after 12 weeks of training. Metabolites measured included glutamateglutamine (Glx), choline-containing compounds (Cho, including glycerophosphocholine and phosphocholine), gamma-aminobutyric acid (GABA), and N-acetyl aspartate and N-acetylaspartyl-glutamate (NAA-NAAG). In total, 11 participants completed MET and 14 completed yogic meditation for this study. Structural MRI analysis showed an interaction between time and group in dACC, indicating a trend towards increased gray matter volume after the MET intervention. 1 H-MRS analysis showed an interaction between time and group in choline-containing compounds in bilateral hippocampus, induced by significant decreases after the MET intervention. Though preliminary, our results suggest that memory training induces structural and neurochemical plasticity in seniors with MCI. Further research is needed to determine whether mind-body interventions like yoga yield similar neuroplastic changes.
International Psychogeriatrics, 2017
ABSTRACTBackground:Global population aging will result in increasing rates of cognitive decline a... more ABSTRACTBackground:Global population aging will result in increasing rates of cognitive decline and dementia. Thus, effective, low-cost, and low side-effect interventions for the treatment and prevention of cognitive decline are urgently needed. Our study is the first to investigate the effects of Kundalini yoga (KY) training on mild cognitive impairment (MCI).Methods:Older participants (≥55 years of age) with MCI were randomized to either a 12-week KY intervention or memory enhancement training (MET; gold-standard, active control). Cognitive (i.e. memory and executive functioning) and mood (i.e. depression, apathy, and resilience) assessments were administered at baseline, 12 weeks and 24 weeks.Results:At baseline, 81 participants had no significant baseline group differences in clinical or demographic characteristics. At 12 weeks and 24 weeks, both KY and MET groups showed significant improvement in memory; however, only KY showed significant improvement in executive functioning. ...
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Psychogeriatrics : the official journal of the Japanese Psychogeriatric Society, Jan 28, 2017
Neurotoxicity associated with amyloid and tau protein aggregation could represent a pathophysiolo... more Neurotoxicity associated with amyloid and tau protein aggregation could represent a pathophysiological cascade that, along with vascular compromise, may predispose individuals to late-life depression (LLD). In LLD, apathy is common, leads to worsening of functioning, and responds poorly to antidepressant treatment. Better understanding of the pathophysiological mechanisms of apathy in LLD would facilitate development of more effective diagnostic and treatment approaches. In this cross-sectional pilot study, we performed positron emission tomography scans after injection of 2-(1-{6-[(2-[(18) F]fluoroethyl)(methyl)-amino]-2-naphthyl}ethylidene) malononitrile ([(18) F]FDDNP), an in vivo amyloid and tau neuroimaging study, in patients with LLD to explore neural correlates of apathy. Sixteen depressed elderly volunteers received clinical assessments and [(18) F]FDDNP positron emission tomography scans. The cross-sectional relationship of [(18) F]FDDNP binding levels with depression (Hami...
Alzheimer's & dementia : the journal of the Alzheimer's Association, Jan 6, 2017
The translocase of outer mitochondrial membrane 40 (TOMM40), which lies in linkage disequilibrium... more The translocase of outer mitochondrial membrane 40 (TOMM40), which lies in linkage disequilibrium with apolipoprotein E (APOE), has received attention more recently as a promising gene in Alzheimer's disease (AD) risk. TOMM40 influences AD pathology through mitochondrial neurotoxicity, and the medial temporal lobe (MTL) is the most likely brain region for identifying early manifestations of AD-related morphology changes. In this study, we examined the effects of TOMM40 using high-resolution magnetic resonance imaging in 65 healthy, older subjects with and without the APOE ε4 AD-risk variant. Examining individual subregions within the MTL, we found a significant relationship between increasing poly-T lengths of the TOMM40 variant and thickness of the entorhinal cortex only in subjects who did not carry the APOE ε4 allele. Our data provide support for TOMM40 variant repeat length as an important contributor to AD-like MTL pathology in the absence of APOE ε4.
The American journal of geriatric psychiatry : official journal of the American Association for Geriatric Psychiatry, Sep 13, 2016
Exercise and diet impact body composition, but their age-related brain effects are unclear at the... more Exercise and diet impact body composition, but their age-related brain effects are unclear at the molecular imaging level. To address these issues, the authors determined whether body mass index (BMI), physical activity, and diet relate to brain positron emission tomography (PET) of amyloid plaques and tau tangles using 2-(1-(6-[(2-[F-18]fluoroethyl)(methyl)amino]-2-naphthyl)ethylidene)malononitrile (FDDNP). Volunteers (N = 44; mean age: 62.6 ± 10.7 years) with subjective memory impairment (N = 24) or mild cognitive impairment (MCI; N = 20) were recruited by soliciting for memory complaints. Levels of physical activity and extent of following a Mediterranean-type diet were self-reported. FDDNP-PET scans assessed plaque/tangle binding in Alzheimer disease-associated regions (frontal, parietal, medial and lateral temporal, posterior cingulate). Mixed models controlling for known covariates examined BMI, physical activity, and diet in relation to FDDNP-PET. MCI subjects with above norm...
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Papers by PRABHA SIDDARTH