Late life depression (LLD) is an important area of research given the growing elderly population. The purpose of this review is to examine the available evidence for the biological basis of LLD. Structural neuroimaging shows specific gray matter structural changes in LLD as well as ischemic lesion burden via white matter hyperintensities. Similarly, specific neuropsychological deficits have been found in LLD. An inflammatory response is another possible underlying contributor to the pathophysiology of LLD. We review the available literature examining these multiple facets of LLD and how each may affect clinical outcome in the depressed elderly.
Late life depression; LLD; Elderly; Ischemic lesion burden; White matter hyperintensities; Neuropsychological factors; Cognitive deficits; Inflammatory markers; Treatment outcome; Structural neuroimaging
Pretreatment brain activity in major depressive disorder correlates with response to antidepressant therapies, including pharmacotherapies and transcranial magnetic stimulation. The purpose of this trial was to examine whether pretreatment regional metabolic activity in selected regions of interest (ROIs) predicts antidepressant response following 12 months of vagus nerve stimulation (VNS) in 15 patients with treatment-resistant major depression (TRMD).
Fluorodeoxyglucose positron emission tomography (FDG PET) was used to assess regional mean relative cerebral metabolic rate for glucose (CMRGlu) in four ROIs (anterior insular, orbitofrontal, anterior cingulate, and dorsolateral prefrontal cortices) at baseline (prior to VNS activation). Depression severity was assessed at baseline and after 12 months of VNS using the Hamilton Depression Rating Scale (HDRS), with response defined as ≥50% reduction in HDRS from baseline.
Baseline CMRGlu in the anterior insular cortex differentiated VNS responders (n = 11) from nonresponders (n = 4) and correlated with HDRS change (r = .64, p = .01). In a regression analysis, lower anterior insular cortex CMRGlu (p = .004) and higher orbitofrontal cortex CMRGlu (p = .047) together predicted HDRS change (R2 = .58, p = .005). In a whole brain, voxel-wise analysis, baseline CMRGlu in the right anterior insular cortex correlated with HDRS change (r = .78, p = .001).
Sample size was small, limiting statistical power; patients remained on their psychiatric medications; study was open-label and uncontrolled.
This preliminary study suggests that pretreatment regional CMRGlu may be useful in predicting response to VNS in TRMD patients.
Vagus nerve stimulation; Depression; Positron emission tomography; Treatment-resistant depression; Fluorodeoxyglucose PET; Treatment response
Traditional T2 weighted MR imaging results are non-specific for the extent of underlying white matter structural abnormalities present in late life depression (LLD). Diffusion tensor imaging provides a unique opportunity to investigate the extent and nature of structural injury, but has been limited by examining only a subset of regions of interest (ROI) and by confounds common to the study of an elderly population, including comorbid vascular pathology. Furthermore, comprehensive correlation of diffusion tensor imaging (DTI) measurements, including axial and radial diffusivity measurements, has not been demonstrated in the late life depression population.
51 depressed and 16 non-depressed, age- and cerebrovascular risk factor- matched elderly subjects underwent traditional anatomic T1 and T2 weight imaging, as well as DTI. The DTI data were skeletonized using tract based spatial statistics (TBSS), and both regional and global analyses were performed.
Widespread structural abnormalities within white matter were detected in the LLD group, accounting for age, gender and education and matched for cerebrovascular risk factors and global T2 white matter hyperintensities (T2WMH). Regional differences were most prominent in uncinate and cingulate white matter and were generally characterized by an increase in radial diffusivity. Age-related changes particularly in the cingulate bundle were more advanced in individuals with LLD relative to controls. Regression analysis demonstrated significant correlations of regional fractional anisotropy and radial diffusivity with five different neuropsychological factor scores. TBSS analysis demonstrated a greater extent of white matter abnormalities in LLD not responsive to treatment, as compared to controls.
White matter integrity is compromised in late life depression, largely manifested by increased radial diffusivity in specific regions, suggesting underlying myelin injury. A possible mechanism for underlying myelin injury is chronic white matter ischemia related to intrinsic cerebrovascular disease. In some regions such as the cingulate bundle, the white matter injury related to late-life depression appears to be independent of and compounded by age-related changes. The correlations with neuropsychological testing indicate the essential effects of white matter injury on functional status. Lastly, response to treatment may depend on the extent of white matter injury, suggesting a need for intact functional networks.
Diffusion tensor imaging; Tract based spatial statistics; Anisotropy; Radial diffusivity
Existing neuroimaging studies of vagus nerve stimulation (VNS) in treatment resistant major depression (TRMD) suggest that many brain regions (e.g., prefrontal cortex, thalamus, cingulate cortex, insular cortex) associated with mood disorders undergo alterations in blood flow/metabolism.
Positron emission tomography (PET oxygen-15 labeled water or PET [15O] H2O) was used to identify changes in regional cerebral blood flow (rCBF) in response to immediate VNS in 13 subjects with TRMD. We hypothesized rCBF changes along the afferent pathway of the vagus and in regions associated with depression (e.g., orbitofrontal cortex, amygdala, insular cortex).
Six 90-second PET [15O] H2O scans were performed on 13 subjects in a VNS off-on sequence. Following normalization for global uptake and realignment to standard atlas space, statistical t-images (p < 0.005) were used to evaluate rCBF change.
VNS induced significant rCBF decreases in the left and right lateral orbitofrontal cortex and left inferior temporal lobe. Significant increases were found in the right dorsal anterior cingulate, left posterior limb of the internal capsule/medial putamen, the right superior temporal gyrus, and the left cerebellar body. Post-hoc analysis found small to moderate correlations between baseline acute change in rCBF and antidepressant response following 12 months of VNS.
Regions undergoing rCBF change in response to acute VNS are consistent with the known afferent pathway of the vagus nerve and models of brain network in depression. Larger studies assessing the correlation between acute stimulation patterns and antidepressant outcomes with VNS are needed.
Vagus nerve stimulation; Depression; Positron emission tomography; Regional blood flow; Treatment-resistant depression
Childhood adversity may influence severity and age of onset of depression, potentially mediated by greater vulnerability to an existing biochemical or neural mechanism. Prior studies have suggested that reduced hippocampal volume is a result of childhood adversity. This study examined the relationship between childhood adversity, hippocampal volumes and clinical characteristics in women who were recruited for depression history rather than abuse experiences. Thirty-one women with remitted unipolar depression and 24 psychiatrically healthy women completed the Childhood Experience of Care and Abuse (Bifulco et al 1994). High resolution MRI scans and hippocampal volumetric determination by stereological assessment were obtained. We found that childhood adversity was associated with a history of recurrent depression and with earlier age of depression onset. We did not find a relationship between childhood adversity and hippocampal volumes in this sample with mild childhood adversity. Our results suggest that the decreased hippocampal volume seen in Major Depressive Disorder may be mediated by additional factors. Further research is needed to more fully understand the interrelationships among childhood adversity, hippocampal morphology, neuroendocrine regulation, and other genetic and environmental factors influencing vulnerability to depression.
Magnetic resonance imaging; depression; abuse; CECA
There has been a dramatic increase in the number of studies using resting state fMRI, a recent addition to imaging analysis techniques. The technique analyzes ongoing low frequency fluctuations in the blood oxygen level dependent (BOLD) signal. Through patterns of spatial coherence, these fluctuations can be used to identify the networks within the brain. Multiple brain networks are present simultaneously and the relationships within and between networks are in constant dynamic flux. Resting state fMRI functional connectivity (rs-fMRI) analysis is increasingly used to detect subtle brain network differences, and in the case of pathophysiology, subtle abnormalities in illnesses such as Alzheimer’s disease (AD). The sequence of events leading up to dementia has been hypothesized to begin many years or decades before any clinical symptoms occur. Here we review the findings across rs-fMRI studies in the spectrum of preclinical AD to clinical AD. In addition, we discuss evidence for underlying preclinical AD mechanisms, including an important relationship between resting state functional connectivity and brain metabolism, and how this results in a distinctive pattern of amyloid plaque deposition in default mode network regions.
fMRI; BOLD; amyloid; precuneus; default mode network (DMN); glycolysis
Amyloid-beta (Aβ) accumulation was evaluated with two PIB PET scans about 2.5 years apart in 146 cognitively normal adults. Seventeen of 21 participants with initially elevated Aβ deposition demonstrated subsequent Aβ plaque growth (approximately 8.0% per year) and none reverted to a state of no Aβ deposits. Ten individuals converted from negative to positive PIB status, based on a threshold of the mean cortical binding potential, representing a conversion rate of 3.1% per year. Individuals with an ε4 allele of apolipoprotein E demonstrated increased incidence of conversion (7.0% per year). Our findings suggest that the major growth in Aβ burden occurs during a preclinical stage of AD, prior to the onset of AD-related symptoms.
preclinical Alzheimer disease; amyloid-beta accumulation; apolipoprotein E; positron emission tomography; [11C]PIB
Differences in white matter structure measured with diffusion tensor imaging (DTI) are associated with late-life depression, but results examining how these differences relate to antidepressant remission are mixed. To better describe these relationships, we examined how one-year change in DTI measures are related to one-year course of depression.
One-year cross-sectional follow-up to a 12-week clinical trial of sertraline.
Outpatients at an academic medical center.
29 depressed and 20 never-depressed elderly subjects. Over the one-year period, 16 depressed subjects achieved and maintained remission, while 13 did not.
One-year change in fractional anisotropy (FA) and diffusivity in frontal white matter, as measured by DTI.
Contrary to our hypotheses, depressed subjects who did not remit over the study interval exhibited significantly less change in anterior cingulate cortex white matter FA than did never-depressed or depressed-remitted subjects. There were no group differences in other frontal or central white matter regions. Moreover, there was a significant positive relationship between change in MADRS and change in anterior cingulate cortex FA, wherein greater interval decline in FA was associated with greater interval decline in MADRS.
Older depressed individuals who remit exhibit white matter changes comparable to what is observed in never-depressed individuals, while nonremitters exhibit significantly less change in anterior cingulate cortex FA. Such a finding may be related to either antidepressant effects on brain structure or the effects of chronic stress on brain structure. Further work is needed to better understand this relationship.
Aging; depression; frontal lobe; anterior cingulate cortex; white matter; diffusion tensor imaging
Identifying high risk populations is an important component of disease prevention strategies. One approach is examining neuroimaging parameters that differ in Alzheimer’s disease (AD), including functional connections known to be disrupted within the “default mode network” (DMN). We have previously shown these same disruptions in cognitively normal elderly, who have amyloid-beta (Aβ) plaques detected using PIB PET imaging, suggesting neuronal toxicity of plaques. Here we sought to determine if pathological effects of apolipoprotein E ε4 (APOE4) genotype could be seen independent of Aβ plaque toxicity by examining resting state fMRI functional connectivity (fcMRI ) in participants without preclinical fibrillar amyloid deposition (PIB−). Cognitively normal participants enrolled in longitudinal studies (n = 100, mean age = 62) who were PIB− were categorized into those with and without an APOE 4 allele and studied using fcMRI. APOE 4 allele carriers (E4+) differed significantly from E4− in functional connectivity of the precuneus to several regions previously defined as having abnormal connectivity in a group of AD participants. These effects were observed prior to any manifestations of cognitive changes and in the absence of brain fibrillar amyloid-beta (Aβ) plaque deposition, suggesting that early manifestations of a genetic effect can be detected using fcMRI and that these changes may antedate the pathological effects of fibrillar amyloid plaque toxicity.
PIB; fMRI; amyloid; Alzheimer’s disease; resting state; precuneus; hippocampus; APOE4
Important functional connections within the “default mode network” (DMN) are disrupted in Alzheimer’s disease (AD), likely from amyloid-beta (Aβ) plaque-associated neuronal toxicity. Here we sought to determine if pathological effects of Aβ amyloid plaques could be seen even in the absence of a task by examining functional connectivity in cognitively normal participants with and without preclinical amyloid deposition.
Participants with Alzheimer’s disease (AD) (n= 35) were compared with 68 cognitively normal participants who were further subdivided by PET PIB imaging into those without evidence of brain amyloid (PIB−) and those with brain amyloid (PIB+) deposition.
Resting state fMRI demonstrated that, compared with the PIB− group, the PIB+ group differed significantly in functional connectivity of the precuneus to hippocampus, parahippocampus, anterior cingulate, dorsal cingulate, gyrus rectus, superior precuneus and visual cortex. These differences were in the same regions, and in the same direction, as differences found in the AD group.
Thus, prior to any manifestations of cognitive or behavioral changes there were differences in resting state connectivity in cognitively normal subjects with brain amyloid deposition, suggesting that early manifestation of Aβ toxicity can be detected using resting state fMRI.
PIB; fMRI; amyloid; Alzheimers Disease; resting state; precuneus; hippocampus
Recently, a novel method for detection of DNA synthesis has been developed based on the incorporation of 5–ethynyl–2′–deoxyuridine (EdU), a thymidine analogue, into cellular DNA and the subsequent reaction of EdU with a fluorescent azide in a copper–catalyzed [3+2] cycloaddition (“Click” reaction). In the present study, we evaluated this method for studying cell proliferation in the adult central nervous system in comparison with the “gold standard” method of 5–bromo–2′–deoxyuridine (BrdU) staining using two behavioral paradigms, voluntary exercise and restraint stress. Our data demonstrate that the number of EdU positive cells in the dentate gyrus of the hippocampus (DG) slightly increased in an EdU dose–dependent manner in both the control and voluntary exercise (running) mouse groups. The number of EdU–labeled cells was comparable to the number of BrdU–labeled cells in both the control and running mice. Furthermore, EdU and BrdU co–localized to the same cells within the DG. Voluntary exercise significantly increased the number of EdU and BrdU positive cells in the DG. In contrast, restraint stress significantly decreased the number of EdU positive cells. The EdU positive cells differentiated into mature neurons. EdU staining is compatible with immunohistochemical staining of other antigens. Moreover, our data demonstrated EdU staining can be combined with BrdU staining, providing a valuable tool of double labeling DNA synthesis, e.g., for tracking the two populations of neurons generated at different time points. In conclusion, our results suggest that EdU staining is a fast, sensitive and reproducible method to study cell proliferation in the central nervous system.
5–ethynyl–2′–deoxyuridine; 5–bromo–2′–deoxyuridine; BrdU; adult neurogenesis; hippocampus
Research on “vascular depression” has used two approaches to subtype late life depression (LLD) based on executive dysfunction or white matter hyperintensity (WMH) severity.
Evaluate the relationship of neuropsychological performance and WMH to clinical response in LLD.
2-site prospective nonrandomized controlled trial.
Outpatient clinics at Washington University and Duke University.
217 subjects age ≥ 60 met DSM-IV criteria for major depression, scored ≥ 20 (MADRS), received vascular risk factor (VRF) scores, neuropsychological testing and MRI scan; were excluded for cognitive impairment or severe medical disorders. Fazekas rating was conducted to grade WMH lesions.
12 weeks of sertraline treatment, titrated by clinical response.
Montgomery-Asberg Depression Rating Scale (MADRS) score over time.
Baseline neuropsychological factor scores correlated negatively with baseline Fazekas scores. A mixed model examined effects of predictor variables on MADRS scores over time. Baseline episodic memory (p = 0.002); language (p = 0.007); working memory (p = 0.01); processing speed (p = 0.0001); executive function factor scores (p = 0.002), and categorical Fazekas ratings (p = 0.049) predicted MADRS scores, controlling for age, education, age of onset and race. Controlling for baseline MADRS scores these factors remained significant predictors of decrease in MADRS scores except working memory and Fazekas ratings. 33% of subjects achieved remission (MADRS ≤ 7). Remitters differed from non-remitters in baseline cognitive processing speed, executive function, language, episodic memory and VRF scores.
Comprehensive neuropsychological function and WMH severity predicted MADRS scores prospectively over a 12 week SSRI treatment course in LLD. Baseline neuropsychological function differentiated remitters from non-remitters and predicted time to remission in a proportional hazards model. Predictor variables correlated highly with VRF severity. These data support the vascular depression hypothesis and highlight the importance of linking subtypes based on neuropsychological function and white matter integrity.
late life depression; antidepressant; neuropsychology; WMH; cognitive deficit; age of onset; vascular risk factors; factor scores
Major depression (MDD) is characterized by altered emotion processing and deficits in cognitive control. In cognitive interference tasks, patients with MDD have shown excessive amygdala activity and under-recruitment of dorsolateral prefrontal cortex (DLPFC). The purpose of this study was to examine the effects of antidepressant treatment on anomalous neural activity in cognitive-control and emotion-processing circuitry.
Functional magnetic resonance imaging was conducted on depressed patients (n=23) (both before and after antidepressant treatment) compared with matched controls (n= 18) while they performed a cognitive task involving attended and unattended fear-related stimuli.
After eight weeks of SSRI antidepressant treatment, patients with depression showed significantly increased DLPFC activity to unattended fear-related stimuli and no longer differed from controls in either DLPFC or amygdala activity.
These results suggest that antidepressant treatment increases DLPFC under-activity during cognitive tasks that include emotional interference.
The sample was fairly homogeneous and this may limit generalizability.
Many recent studies have identified white matter abnormalities in late life depression (LLD). These abnormalities include an increased volume of discrete white matter lesions (hyperintensities on T2-weighted imaging) and changes in the diffusion tensor properties of water. However, no study of LLD to date has examined the integrity of white matter outside of discrete lesions, i.e., in normal appearing white matter. We performed T1- and T2-weighted imaging as well as diffusion tensor imaging (DTI) in depressed elderly subjects (n=73) and non-depressed control subjects (n=23) matched for age and cerebrovascular risk factors. The structural images were segmented into white matter, gray matter, cerebrospinal fluid and discrete white matter lesions. DTI parameters were calculated in white matter regions of interest after excluding the white matter lesions. Widespread LLD vs. control group differences were found, particularly in prefrontal regions, where the DTI abnormalities correlated with cognitive processing speed. These results suggest that further investigation is warranted to determine the basic pathophysiology and potential reversibility of LLD.
Depression; MRI; Diffusion Tensor Imaging; Geriatrics; segmentation; LLD
Vitamin D deficiency is common in older adults and is more prevalent among persons with darker pigmented skin. The detrimental effects of vitamin D deficiency on the bone are widely known; however, recent data suggest that vitamin D deficiency may contribute to other disorders, including low mood, cognitive impairment, and impaired mobility.
The purpose of this study was to determine whether nonskeletal diseases such as depression, cognitive impairment, and physical disability, which have been associated with vitamin D deficiency, are more commonly seen in older African Americans.
In a cross-sectional study of 60 older adults (30 African Americans and 30 European Americans), vitamin D status, cognitive performance, physical performance, and bone mineral density (BMD) were assessed. Differences between groups and differences between those with vitamin D deficiency and those with normal vitamin D levels were tested.
African Americans had a lower mean 25-hydroxyvitamin D level (17.98 ng/ml; SD, 6.9) compared to European Americans (25.20 ng/ml; SD, 7.0; p < .0001). Participants with vitamin D deficiency performed worse on a measure of cognitive performance, the Short Blessed Test (10.87 vs 6.31; p = .016); the Physical Performance Test (PPT) (27.00 vs 28.96; p = .039); and had lower BMD (0.823 vs 0.914; p = .005) and t scores (−1.29 vs −0.72; p = .008) of the hip. Among African Americans, vitamin D deficiency was associated with worse cognitive performance and lower BMD of the hip.
Vitamin D deficiency in older African Americans was associated with worse cognitive performance and lower BMD of the hip.
vitamins and minerals; African Americans; cognitive functioning; bone
Older adults with depression often present with signs and symptoms indicative of functional or cognitive impairment. These somatic symptoms make evaluating and treating depression in older adults more complex. Late life depression (LLD), depression in adults over the age of 65, is more frequently associated with cognitive changes. Cognitive impairment in LLD may be a result of the depressive disorder or an underlying dementing condition. Memory complaints are also common in older adults with depression. There is a wide range of cognitive impairment in LLD including decreased central processing speed, executive dysfunction, and impaired short-term memory. The etiology of cognitive impairment in LLD may include cerebrovascular disease, a significant risk factor for LLD, which likely interrupts key pathways between frontal white matter and subcortical structures important in mood regulation. Because depressive symptoms often coexist with dementia, it is important to determine the temporal relationship between depressive symptoms and cognitive change. If depressive symptoms pre-date the cognitive impairment and cognitive symptoms are mild and temporary, LLD is the likely etiology of the cognitive impairment. If cognitive changes appear prior to depressive symptoms and persist after LLD is successfully treated, an underlying dementia is more likely. Clinicians should be exclude common conditions such as thyroid disease which can contribute to depressive symptoms and cognitive impairment prior to treating LLD. Both antidepressants and psychotherapy can be effective in treating LLD. Subsequent evaluations following treatment should also reassess cognition.
late life depression; cognitive impairment; diagnosis; treatment; cognition
Neuroanatomic features associated with antidepressant treatment outcomes in older depressed individuals are not well established. This study used diffusion tensor imaging to examine frontal white matter structure in depressed subjects undergoing a 12-week trial of sertraline. We hypothesized that remission would be associated with higher frontal anisotropy measures, and failure to remit with lower anisotropy.
74 subjects with Major Depressive Disorder and age 60 years or older were enrolled in a twelve-week open-label trial of sertraline and completed clinical assessments and 1.5T magnetic resonance brain imaging. The apparent diffusion coefficient (ADC) and fractional anisotropy (FA) were measured in regions of interest placed in the white matter of the dorsolateral prefrontal cortex, anterior cingulate cortex, and corpus callosum. Differences in ADC and FA values between subjects who did and did not remit to treatment over the study period were assessed using generalized estimating equations, controlling for age, sex, medical comorbidity and baseline depression severity.
Subjects who did not remit to sertraline exhibited higher FA values in the superior frontal gyri and anterior cingulate cortices bilaterally. There were no statistically significant associations between ADC measures and remission.
Failure to remit to sertraline is associated with higher frontal FA values. Functional imaging studies demonstrate that depression is characterized by functional disconnection between frontal and limbic regions. Those individuals where this disconnection is related to structural changes as detected by DTI may be more likely to respond to antidepressants.
Major depression is characterized by a negativity bias: an enhanced responsiveness to, and memory for, affectively negative stimuli. However it is not yet clear whether this bias represents (1) impaired top-down cognitive control over affective responses, potentially linked to deficits in dorsolateral prefrontal cortex function; or (2) enhanced bottom-up responses to affectively-laden stimuli that dysregulate cognitive control mechanisms, potentially linked to deficits in amygdala and anterior cingulate function.
We used an attentional interference task using emotional distracters to test for top-down versus bottom-up dysfunction in the interaction of cognitive-control circuitry and emotion-processing circuitry. A total of 27 patients with major depression and 24 controls were tested. Event-related functional magnetic resonance imaging was carried out as participants directly attended to, or attempted to ignore, fear-related stimuli.
Compared to controls, patients with depression showed an enhanced amygdala response to unattended fear-related stimuli (relative to unattended neutral). By contrast, control participants showed increased activity in right dorsolateral prefrontal cortex (Brodmann areas 46/9) when ignoring fear stimuli (relative to neutral), which the patients with depression did not. In addition, the depressed participants failed to show evidence of error-related cognitive adjustments (increased activity in bilateral dorsolateral prefrontal cortex on post-error trials), but the control group did show them.
These results suggest multiple sources of dysregulation in emotional and cognitive control circuitry in depression, implicating both top-down and bottom-up dysfunction.
To test the hypothesis that the degree vascular burden and/or age of onset may influence the degree to which cognition can improve during the course of treatment in late life depression.
Measurement of cognition both prior to and following 12-weeks of treatment with Sertraline.
University Medical Centers (Washington University and Duke University)
166 individuals with late life depression.
The cognitive tasks were grouped into five domains (language, processing speed, working memory, episodic memory, and executive function). We measured vascular risk using the Framingham Stroke Risk Profile measure. We measured T2 based white matter hyperintensities using the Fazekas criteria.
Both episodic memory and executive function demonstrated significant improvement among adults with late life depression during treatment with sertraline. Importantly, older age, higher vascular risk scores, and lower baseline Mini-Mental state exam scores predicted less change in working memory. Further, older age, later age of onset, and higher vascular risk scores predicted less change in executive function.
These results have important clinical implications, in that they suggest that a regular assessment of vascular risk in older adults with depression is necessary as a component of treatment planning and in predicting prognosis, both for the course of the depression itself and for the cognitive impairments that often accompany depression in later life.
Cognition; Vascular Depression; Treatment; white matter
An Alzheimer’s fMRI study has motivated us to evaluate inter-regional correlations between groups. The overall objective is to assess inter-regional correlations at a resting-state with no stimulus or task. We propose using a generalized estimating equation (GEE) transition model and a GEE marginal model to model the within-subject correlation for each region. Residuals calculated from the GEE models are used to correlate brain regions and assess between group differences. The standard pooling approach of group averages of the Fisher-z transformation assuming temporal independence is a typical approach used to compare group correlations. The GEE approaches and standard Fisher-z pooling approach are demonstrated with an Alzheimer’s disease (AD) connectivity study in a population of AD subjects and healthy control subjects. We also compare these methods using simulation studies and show that the transition model may have better statistical properties.
The loss of new investigators from academic science is a “crisis” placing the future of biomedical science at risk. Failure to obtain independent funding contributes significantly to attrition from the NIH career path. The purpose of this paper is to describe the components and outcomes of the Advanced Research Institute (ARI) in Geriatric Mental Health, an NIMH grant-funded national program that targets successful transition of new investigators to independence.
The authors first describe the program participants and key components. They then compare the record of federal grant funding, derived from the NIH Reporter database, of the first four cohorts (2004–2007; n=42) to those of all NIMH mentored career development (K) awardees funded 2001–2005 (n=404).
As of January 2010, 45.2% of Scholars had achieved R01 funding. Nearly 70% obtained some NIH grant (not including K or small grants). Among all NIMH mentored K awardees, ARI Scholars were 2.36 (p=0.048) more likely to achieve an R01; outcomes were similar (OR=2.42, p= .045) when including R34s.
Based on objective outcomes, the Advanced Research Institute (ARI) in Geriatric Mental Health offers an effective model to promoting successful transition of new investigators to independence. While organized around a specific public health and scientific need, ARI’s components are generalizable to other fields. Further, the inclusion of biological, clinical and services researchers into a single program promotes translational science. Thus ARI is one tool to stemming attrition from the NIH career path and promoting the next generation of science.