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1.  Patterns of Reduced Cortical Thickness in Late Life Depression and Relationship to Psychotherapeutic Response 
Cortical atrophy has been associated with late life depression (LLD) and recent findings suggest that reduced right hemisphere cortical thickness is associated with familial risk for major depressive disorder but cortical thickness abnormalities in LLD have not been explored. Further, cortical atrophy has been posited as a contributor to poor antidepressant treatment response in LLD but the impact of cortical thickness on psychotherapy response is unknown. This study was conducted to evaluate patterns of cortical thickness in LLD and in relation to psychotherapy treatment outcomes.
Participants included 22 individuals with LLD and 12 age matched comparison subjects. LLD participants completed 12 weeks of psychotherapy and treatment response was defined as a 50% reduction in depressive symptoms. All participants participated in Magnetic Resonance Imaging (MRI) of the brain and cortical mapping of grey matter tissue thickness was calculated.
LLD individuals demonstrated thinner cortex than controls prominently in the right frontal, parietal, and temporal brain regions. Eleven participants (50%) exhibited positive psychotherapy response after 12 weeks of treatment. Psychotherapy non-responders demonstrated thinner cortex in bilateral posterior cingulate and parahippocampal cortices, left paracentral, precuneus, cuneus, and insular cortices, and the right medial orbito-frontal and lateral occipital cortices relative to treatment responders.
Our findings suggest more distributed right hemisphere cortical abnormalities in LLD than have been previously reported. Additionally, our findings suggest that reduced bilateral cortical thickness may be an important phenotypic marker of individuals at higher risk for poor response to psychotherapy.
PMCID: PMC3732520  PMID: 23567394
2.  Pattern of Cognitive Impairment in Older Veterans with Post Traumatic Stress Disorder Evaluated at a Memory Disorders Clinic 
We determined the pattern of clinically significant cognitive impairment (CI) among older veterans with Post Traumatic Stress Disorder (PTSD) evaluated in a memory disorders clinic.
Data was collected from 19 ethnically diverse veterans. Cognitive functioning in six domains (verbal learning, memory, attention, language, executive functioning, and information processing speed) was assessed.
The majority of veterans (57%) demonstrated CI on a measure of single trial list learning, 44% exhibited CI on short delay memory for lists, and 31% exhibited CI in long delay memory for lists. CI on measures of memory for stories (14%) and executive functioning (6%) were less common and none of the participants demonstrated CI on measures of attention, language, or information processing speed.
CI on measures of single trial list learning and memory for lists are common in older PTSD patients evaluated in a memory disorders clinic and are likely to contribute to functional deficits.
PMCID: PMC3685474  PMID: 22213461
Cognitive deficits; cognitive impairment; Post Traumatic Stress Disorder; older adults; veterans; memory; learning; single trial learning; executive dysfunction; information processing speed; attention; language
3.  Longitudinal Stability of Subsyndromal Symptoms of Depression in Individuals with Mild Cognitive Impairment: Relationship to Conversion to Dementia after Three Years 
To evaluate the degree to which longitudinal stability of subsyndromal symptoms of depression (SSD) is associated with conversion to dementia in patients with Mild Cognitive Impairment (MCI).
Data from 405 MCI participants from the Alzheimer's Disease Neuroimaging Initiative (ADNI) study were analyzed. Participants were evaluated at baseline and 12 month intervals over three years. Participants were designated as MCI Converters if dementia was diagnosed within 3 years or as Cognitively Stable MCI if dementia was not diagnosed during this interval. SSD were evaluated utilizing the 15-item Geriatric Depression Scale (GDS). Endorsement of specific SSD at baseline and the stability of SSD over 36 months were compared between the two MCI groups.
Baseline symptom endorsement and stability of total GDS scores did not differentiate MCI groups. Worsening of 4 individual items from the GDS over time (memory problems, feelings of helplessness, loss of interest, and preference for staying at home) differentiated MCI converters from cognitively stable MCI (p <0.05 for all). However, only increased endorsement of memory symptoms over time was associated with progression to dementia after controlling for other clinical variables (p=0.05).
SSD in MCI participants largely consist of cognitive symptoms and activity limitations and the stability of SSD over time differentiated the MCI groups better than baseline endorsement of symptoms. However, the only significant predictor of conversion to dementia was increased endorsement of memory problems, which likely represents insight into cognitive problems more than depressive symptomatology in MCI individuals.
PMCID: PMC3685477  PMID: 21744390
subsyndromal depression; longitudinal stability; mild cognitive impairment; insight; dementia
4.  Incidence and Documentation of Cognitive Impairment Among Older Adults With Severe Mental Illness in a Community Mental Health Setting 
Cognitive impairments among older adults are commonly linked to poor medical and psychiatric treatment adherence, increased disability, and poor health outcomes. Recent investigations suggest that cognitive impairments are frequently not recognized by healthcare providers and are often poorly documented in medical records. Older adults utilizing services at community mental health centers have numerous risk factors for developing cognitive impairment. Few studies have explored the incidence and documentation of cognitive impairments in this patient population.
Data were collected from 52 ethnically diverse older adults with severe mental illness who were participating in treatment at a large community mental health center. Cognitive impairment was diagnosed by neuropsychologists utilizing the Mattis Dementia Rating Scale-2 (DRS). Measures of depression severity and substance abuse history were also obtained. An age and education corrected DRS total score falling at or below the tenth percentile was used as the criteria for diagnosing cognitive impairment. A medical chart review was subsequently conducted to determine the documentation of cognitive impairments among this patient population.
Cognitive impairment was exhibited by 60% of participants and documented in medical charts for 17% of the sample.
Preliminary data suggests that cognitive impairment is common in individuals with severe mental illness treated at community mental health centers, but these cognitive impairments are not well recognized or documented. The impact of cognitive impairment on psychiatric treatment and case management among community mental health patients is therefore poorly understood.
PMCID: PMC3239216  PMID: 19092314
Cognitive impairment; severe mental illness; depression; documentation; community mental health
5.  The Sensitivity and Specificity of Cognitive Screening Instruments to Detect Cognitive Impairment in Older Adults With Severe Psychiatric Illness 
Older adults with severe psychiatric illness are often treated at community mental health centers (CMHCs) and these individuals commonly have numerous risk factors for cognitive impairment (CI). Brief cognitive screening instruments are frequently used to evaluate cognitive functioning in CMHCs, but the validity of these measures for detecting CI has not been adequately evaluated in this patient population.
To determine the sensitivity and specificity of 2 cognitive screening measures (the Mini-Mental Status Examination [MMSE] and the Stroop Color and Word Test [SCWT]) for detecting CI in a sample of older adults with severe psychiatric illness.
Data were collected from 52 older adults receiving services at a CMHC. Diagnosis of CI was made by a neuropsychologist. Sensitivity and specificity coefficients for 2 cutoff scores for the MMSE and the SCWT were calculated.
A cutoff score of 25 on the MMSE yielded a sensitivity of 43.3% and a specificity of 90.4% for detecting CI, whereas a cutoff score of 21 yielded sensitivity of 13.1% and 100% specificity. Using an age- and education-corrected scaled score (SS) on the SCWT falling at or below 7 as the criterion the SCWT had 88.8% sensitivity and 36.8% specificity, whereas a cutoff score of 5 or below yielded sensitivity of 59.2% and specificity of 57.8%.
Overall, the MMSE was found to be the more clinically useful cognitive screening tool for use in CMHC. Yet, because of the poor sensitivity of the MMSE for detecting CI in this patient population, alternative screening methods should be explored.
PMCID: PMC3239217  PMID: 20101070
cognitive impairment; geriatric; Community Mental Health Center; Mini-Mental State Examination; Stroop Color and Word Test; sensitivity; specificity; severe psychiatric illness; depression; schizophrenia
6.  The Effect of Cognitive Impairment on Mental Healthcare Costs for Individuals With Severe Psychiatric Illness 
This study was conducted to determine the effect of cognitive impairment (CI) on mental healthcare costs for older low-income adults with severe psychiatric illness.
Data were collected from 62 ethnically diverse low-income older adults with severe psychiatric illness who were participating in day programming at a large community mental health center. CI was diagnosed by a neuropsychologist utilizing the Mattis Dementia Rating Scale-Second Edition and structured ratings of functional impairment (Clinical Dementia Rating Scale). Mental healthcare costs for 6, 12, and 24-month intervals before cognitive assessments were obtained for each participant. Substance abuse history was evaluated utilizing a structured questionnaire, depression symptom severity was assessed utilizing the Hamilton Depression Rating Scale, and psychiatric diagnoses were obtained through medical chart abstraction.
CI was exhibited by 61% of participants and was associated with significantly increased mental healthcare costs during 6, 12, and 24-month intervals. Results of a regression analysis indicated that ethnicity and CI were both significant predictors of log transformed mental healthcare costs over 24 months with CI accounting for 13% of the variance in cost data.
CI is a significant factor associated with increased mental healthcare costs in patients with severe psychiatric illness. Identifying targeted interventions to accommodate CI may lead to improving treatment outcomes and reducing the burden of mental healthcare costs for individuals with severe psychiatric illness.
PMCID: PMC3239219  PMID: 20808129
Mental healthcare costs; cognitive impairment; severe psychiatric illness; schizophrenia; major depression; community mental health
7.  Problem solving therapy for the treatment of depression for a patient with Parkinson’s disease and mild cognitive impairment: a case study 
The present investigation reports on the use of problem solving therapy (PST) to treat depression in an 83-year-old woman with Parkinson’s disease (PD) and concurrent mild cognitive impairment (MCI). A neuropsychological evaluation was conducted prior to the intervention and the patient demonstrated mild deficits of executive functioning and memory. The PST treatment consisted of 12 one-hour sessions that occurred weekly. Depressive symptoms were evaluated using the Hamilton Depression Rating scale and the Montgomery-Asberg Depression rating scale. At a post-treatment assessment (week 12), clinician assessment indicated that the client no longer met criteria for MDD. Weekly depression severity ratings showed significant reduction in severity of depressive symptoms over 12 weeks. Results at 1-month and 6-month follow-up demonstrated that the therapeutic gains were not only maintained, but that the client continued to improve. These results suggest that PST may be an effective treatment for the treatment of depression for individuals with a PD and concurrent MCI.
PMCID: PMC2671813  PMID: 19412485
problem solving therapy; psychotherapy; mild cognitive impairment; executive dysfunction; memory; Parkinson’s disease; depression; geriatric
8.  Dysexecutive and amnesic AD subtypes defined by single indicator and modern psychometric approaches: relationships with SNPs in ADNI 
Brain imaging and behavior  2012;6(4):649-660.
Previous investigators have suggested the existence of distinct cognitive phenotypes of Alzheimer’s disease (AD): a dysexecutive subgroup with executive functioning worse than memory and an amnesic subgroup with memory worse than executive functioning.
We evaluated data from the AD Neuroimaging Initiative. We assigned people with AD to dysexecutive and amnesic subgroups using single indicators, and analogously using the ADNI-Mem and ADNI-EF composite scores developed using modern psychometric approaches. We evaluated associations between subgroup membership, APOE genotype, and SNPs associated with AD, and brain vascular disease defined as white matter hyperintensities (WMH) and MRI-identified infarcts. We hypothesized that APOE ε4 and alleles associated with higher risk for AD would predict amnesic subgroup membership; alleles associated with higher WMH or infarct burden would predict dysexecutive subgroup membership.
Classification agreement between the two approaches was only fair (kappa = 0.23). There was no relationship between APOE alleles and the dysexecutive or amnesic phenotypes defined by either categorization approach. There were 58 AD-related and 25 WMH- or infarct-related SNPs for which odds ratios were > 1.5 or < 0.67 for dysexecutive vs. amnesic subgroup defined by either categorization approach. Higher proportions of SNPs had odds ratios in the hypothesized direction for the subgroups defined by the modern psychometric approach for AD-related (58% vs. 38%, p-value < 0.001) and brain vascular disease-related SNPs (48 vs. 32%, p-value = 0.01).
Genetic variation may underlie differential performance in memory and executive functioning among people with AD. Modern psychometric composite scores produced group assignments with more SNP associations in the hypothesized direction.
PMCID: PMC3532526  PMID: 23161456
Memory; executive functioning; Alzheimer’s disease; phenotype; genetic analyses; psychometrics
9.  A composite score for executive functioning, validated in Alzheimer’s Disease Neuroimaging Initiative (ADNI) participants with baseline mild cognitive impairment 
Brain imaging and behavior  2012;6(4):517-527.
The Alzheimer’s Disease Neuroimaging Initiative (ADNI) measures abilities broadly related to executive function (EF), including WAIS-R Digit Symbol Substitution, Digit Span Backwards, Trails A and B, Category Fluency, and Clock Drawing. This study investigates whether a composite executive function measure based on these multiple indicators has better psychometric characteristics than the widely used individual components. We applied item response theory methods to 800 ADNI participants to derive an EF composite score (ADNI-EF) from the above measures. We then compared ADNI-EF with component measures in 390 longitudinally-followed participants with mild cognitive impairment (MCI) with respect to: (1) Ability to detect change over time; (2) Ability to predict conversion to dementia; (3) Strength of cross-sectional association with MRI-derived measures of structures involved in frontal systems, and (4) Strength of baseline association with cerebrospinal fluid (CSF) levels of amyloid β1-42, total tau, and phosphorylated tau181P. ADNI-EF showed the greatest change over time, followed closely by Category Fluency. ADNI-EF needed a 40 % smaller sample size to detect change. ADNI-EF was the strongest predictor of AD conversion. ADNI-EF was the only measure significantly associated with all the MRI regions, though other measures were more strongly associated in a few of the regions. ADNI-EF was associated with all the CSF measures. ADNI-EF appears to be a useful composite measure of EF in MCI, as good as or better than any of its composite parts. This study demonstrates an approach to developing a psychometrically sophisticated composite score from commonly-used tests.
PMCID: PMC3684181  PMID: 22644789
Executive function; Mild cognitive impairment; Item response theory; Composite scores
10.  Development and assessment of a composite score for memory in the Alzheimer’s Disease Neuroimaging Initiative (ADNI) 
Brain imaging and behavior  2012;6(4):502-516.
We sought to develop and evaluate a composite memory score from the neuropsychological battery used in the Alzheimer’s Disease (AD) Neuroimaging Initiative (ADNI). We used modern psychometric approaches to analyze longitudinal Rey Auditory Verbal Learning Test (RAVLT, 2 versions), AD Assessment Schedule - Cognition (ADAS-Cog, 3 versions), Mini-Mental State Examination (MMSE), and Logical Memory data to develop ADNI-Mem, a composite memory score. We compared RAVLT and ADAS-Cog versions, and compared ADNI-Mem to AVLT recall sum scores, four ADAS-Cog-derived scores, the MMSE, and the Clinical Dementia Rating Sum of Boxes. We evaluated rates of decline in normal cognition, mild cognitive impairment (MCI), and AD, ability to predict conversion from MCI to AD, strength of association with selected imaging parameters, and ability to differentiate rates of decline between participants with and without AD cerebrospinal fluid (CSF) signatures. The second version of the RAVLT was harder than the first. The ADAS-Cog versions were of similar difficulty. ADNI-Mem was slightly better at detecting change than total RAVLT recall scores. It was as good as or better than all of the other scores at predicting conversion from MCI to AD. It was associated with all our selected imaging parameters for people with MCI and AD. Participants with MCI with an AD CSF signature had somewhat more rapid decline than did those without. This paper illustrates appropriate methods for addressing the different versions of word lists, and demonstrates the additional power to be gleaned with a psychometrically sound composite memory score.
PMCID: PMC3806057  PMID: 22782295
Memory; psychometrics; longitudinal analysis; cognition; hippocampus
11.  Different associations of white matter lesions with depression and cognition 
BMC Neurology  2012;12:83.
To test the hypothesis that white matter lesions (WML) are primarily associated with regional frontal cortical volumes, and to determine the mediating effects of these regional frontal cortices on the associations of WML with depressive symptoms and cognitive dysfunction.
Structural brains MRIs were performed on 161 participants: cognitively normal, cognitive impaired but not demented, and demented participants. Lobar WML volumes, regional frontal cortical volumes, depressive symptom severity, and cognitive abilities were measured. Multiple linear regression analyses were used to identify WML volume effects on frontal cortical volume. Structural equation modeling was used to determine the MRI-depression and the MRI-cognition path relationships.
WML predicted frontal cortical volume, particularly in medial orbirtofrontal cortex, irrespective of age, gender, education, and group status. WML directly predicted depressive score, and this relationship was not mediated by regional frontal cortices. In contrast, the association between WML and cognitive function was indirect and mediated by regional frontal cortices.
These findings suggest that the neurobiological mechanisms underpinning depressive symptoms and cognitive dysfunction in older adults may differ.
PMCID: PMC3482604  PMID: 22920586
Leukoaraiosis; Depression; Cognition; Frontal lobe; Mediation
12.  Patterns of Alcohol and Drug Use Among Depressed Older Adults Seeking Outpatient Psychiatric Services 
Alcohol and drug use and related problems may compromise depression treatment, and older adults may be especially at risk for poor outcomes. However, alcohol and drug use among older adults have not been studied in settings in which depression treatment is provided. This study examined the prevalence and clinical and demographic correlates of alcohol and drug use and misuse of prescription drugs among adults with depression seeking outpatient psychiatric care (excluding chemical dependency treatment).
The sample included 154 older adults (age 60 years and older who scored ≥10 on the Beck Depression Inventory-II [BDI-II] at intake). Participants also completed alcohol and drug use questions and the Short Michigan Alcohol Screening Test.
Recent alcohol and drug use, heavy episodic drinking, and history of alcohol-related problems were common. Alcohol use in the prior 30 days was reported by 53% of men and 50% of women. Cannabis use in the prior 30 days was reported by 12% of men and 4% of women; and misuse of sedatives in the prior 30 days was reported by 16% of men and 9% of women. In exact logistic regression, higher BDI-II score was associated with cannabis use (odds ratio = 15.8, 95% confidence interval = 2.0-734.0, exact p = 0.003).
Older adults with depression are likely to present for treatment with a range of concurrent alcohol and drug use patterns, including cannabis use and misuse of prescription medication. Clinicians should evaluate depressed patients for substance use and related problems and consider appropriate interventions.
PMCID: PMC3242695  PMID: 21788921
Depression; alcohol; cannabis; prescription drug misuse
13.  Problem Solving Therapy and Supportive Therapy in Older Adults with Major Depression and Executive Dysfunction: Effect on Disability 
Archives of general psychiatry  2011;68(1):33-41.
Older patients with depression and executive dysfunction represent a population with significant disability and high likelihood of failing pharmacotherapy.
To examine whether Problem Solving Therapy (PST) reduces disability more than Supportive Therapy (ST) in older patients with depression and executive dysfunction, and whether this effect is mediated by improvement in depressive symptoms.
Randomized controlled trail, with participant recruitment from 12/02-11/07 and follow-up for 36 weeks.
Weill Cornell and University of California, San Francisco.
Adults (>59 years) with major depression and executive dysfunction.
12 sessions of either PST modified for older depressed adults with executive impairment, or ST.
Main Outcome Measure
Disability as quantified by the World Health Organization Assessment Schedule II (WHODAS II)-12 item form.
653 individuals were referred to this study, 221 of whom met criteria and were randomized to PST or ST. PST and ST led to comparable improvement of disability in the first 6 weeks of treatment, but a more prominent reduction in PST participants at weeks 9 and 12. The difference between PST and ST was greater in patients with greater cognitive impairment and higher number of previous episodes. Reduction in disability paralleled reduction in depressive symptoms. The therapeutic advantage of PST over ST in reducing depression was in part due to greater reduction of disability by PST. While disability increased during the 24 weeks following the end of treatment, the advantage of PST over ST-treated patients was retained.
This study suggests that PST is more effective than ST in reducing disability in older patients with major depression and executive dysfunction, and its benefits were retained after the end of treatment. The clinical value of this finding is that PST may be a treatment alternative in an older patient population likely to be resistant to pharmacotherapy.
PMCID: PMC3018861  PMID: 21199963
14.  Plasma biomarkers of depressive symptoms in older adults 
Translational Psychiatry  2012;2(1):e65-.
The pathophysiology of negative affect states in older adults is complex, and a host of central nervous system and peripheral systemic mechanisms may play primary or contributing roles. We conducted an unbiased analysis of 146 plasma analytes in a multiplex biochemical biomarker study in relation to number of depressive symptoms endorsed by 566 participants in the Alzheimer's Disease Neuroimaging Initiative (ADNI) at their baseline and 1-year assessments. Analytes that were most highly associated with depressive symptoms included hepatocyte growth factor, insulin polypeptides, pregnancy-associated plasma protein-A and vascular endothelial growth factor. Separate regression models assessed contributions of past history of psychiatric illness, antidepressant or other psychotropic medicine, apolipoprotein E genotype, body mass index, serum glucose and cerebrospinal fluid (CSF) τ and amyloid levels, and none of these values significantly attenuated the main effects of the candidate analyte levels for depressive symptoms score. Ensemble machine learning with Random Forests found good accuracy (∼80%) in classifying groups with and without depressive symptoms. These data begin to identify biochemical biomarkers of depressive symptoms in older adults that may be useful in investigations of pathophysiological mechanisms of depression in aging and neurodegenerative dementias and as targets of novel treatment approaches.
PMCID: PMC3309547  PMID: 22832727
Alzheimer's disease neuroimaging initiative; biochemical biomarker; geriatric depression; mild cognitive impairment
15.  Recruitment of African Americans and Asian Americans with Late Life Depression and Mild Cognitive Impairment 
The purpose of this study was to compare the relative effectiveness of several different strategies for recruiting elderly Asians, African Americans, and Caucasians to participate in mental health research.
A total of 35 African American, 24 Asian American, and 215 Caucasian participants were phone-screened for potential enrollment into a University of California, San Francisco Department of Psychiatry treatment outcome study for older adults (60+ years of age) with major depression and mild cognitive impairment.
The methods by which participants were recruited were recorded, coded into composite categories, and statistically analyzed to determine whether certain recruitment strategies were disproportionately effective for recruiting participants from the three racial groups.
Fisher's exact test analyses revealed that Asians and African Americans were significantly less likely than Caucasians to be recruited through mental health-based methods, and African Americans were significantly more likely than Caucasians and Asians to be recruited via referrals rather than solicitations. Logistic regression, which controlled for potential confounds, largely supported these findings.
Findings suggest that the recruitment of elderly African or Asian Americans into mental health treatment outcome research can be facilitated by a flexible consumer-oriented strategy that integrates multiple recruitment methods. Establishing study credibility through non-mental health media and professional referral sources may be especially effective in engaging the participation of elderly Asian Americans; and cultivating ongoing relationships with key gatekeepers, who can observe benefits to the community, may be particularly effective in recruiting elderly African Americans.
PMCID: PMC2898912  PMID: 20220590
recruitment; Asian; African American; minority; late life depression; cognitive impairment; executive dysfunction
16.  Problem-Solving Therapy and Supportive Therapy in Older Adults With Major Depression and Executive Dysfunction 
The American journal of psychiatry  2010;167(11):1391-1398.
The purpose of this study was to determine whether problem-solving therapy is an effective treatment in older patients with depression and executive dysfunction, a population likely to be resistant to antidepressant drugs.
Participants were adults age 60 and older with major depression and executive dysfunction. Problem-solving therapy was modified to be accessible to this population. Participants were randomly assigned to 12 weekly sessions of problem-solving therapy or supportive therapy and assessed at weeks 3, 6, 9, and 12.
Of the 653 individuals referred for this study, 221 met selection criteria and were enrolled in the study. Reduction of depressive symptom severity was comparable for the two treatment groups during the first 6 weeks of treatment, but at weeks 9 and 12 the problem-solving therapy group had a greater reduction in symptom severity, a greater response rate, and a greater remission rate than the supportive therapy group (response rates at week 9: 47.1% and 29.3%; at week 12: 56.7% and 34.0%; remission rates at week 9: 37.9% and 21.7%; at week 12: 45.6% and 27.8%). Problem-solving therapy yielded one additional response or remission over supportive therapy for every 4.4–5.6 patients by the end of the trial.
These results suggest that problem-solving therapy is effective in reducing depressive symptoms and leading to treatment response and remission in a considerable number of older patients with major depression and executive dysfunction. The clinical value of this finding is that problem-solving therapy may be a treatment alternative in an older patient population likely to be resistant to pharmacotherapy.
PMCID: PMC2998516  PMID: 20516155

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