Joseph S. Goveas

Changes in regional cerebral blood flow and functional connectivity in the cholinergic pathway associated with cognitive performance in subjects with mild Alzheimer's disease after 12-week donepezil treatment.

Acetylcholinesterase inhibitors (AChEIs), such as donepezil, have been shown to improve cognition in mild to moderate Alzheimers disease (AD) patients. In this paper, our goal is to determine the relationship between altered cerebral blood flow (CBF) and intrinsic functional network connectivity changes in mild AD patients before and after 12-week donepezil treatment. An integrative neuroimaging approach was employed by combining pseudocontinuous arterial spin labeling (pCASL) MRI and resting-state functional MRI (R-fMRI) methods to determine the changes in CBF and functional connectivity (FC) in the cholinergic pathway. Linear regression analyses determined the correlations of the regional CBF alterations and functional connectivity changes with cognitive responses. These were measured with the Mini-Mental Status Examination (MMSE) scores and Alzheimers disease Assessment Scale-Cognitive subscale (ADAS-cog) scores. Our results show that the regional CBF in mild AD subjects after donepezil treatment was significantly increased in the middle cingulate cortex (MCC) and posterior cingulate cortex (PCC), which are the neural substrates of the medial cholinergic pathway. In both brain regions, the baseline CBF and its changes after treatment were significantly correlated with the behavioral changes in ADAS-cog scores. The intrinsic FC was significantly enhanced in the medial cholinergic pathway network in the brain areas of the parahippocampal, temporal, parietal and prefrontal cortices. Finally, the FC changes in the medial prefrontal areas demonstrated an association with the CBF level in the MCC and the PCC, and also were correlated with ADAS-cog score changes. These findings indicate that regional CBF and FC network changes in the medial cholinergic pathway were associated with cognitive performance. It also is suggested that the combined pCASL-MRI and R-fMRI methods could be used to detect regional CBF and FC changes when using drug treatments in mild AD subjects.

Depressive symptoms and incidence of mild cognitive impairment and probable dementia in elderly women: the Women's Health Initiative Memory Study.

OBJECTIVES: To examine whether significant depressive symptoms in postmenopausal women increases the risk of subsequent mild cognitive impairment (MCI) and dementia.

Influence of type 2 diabetes on brain volumes and changes in brain volumes: Results from the Women's Health Initiative Magnetic Resonance Imaging Studies

OBJECTIVE To study how type 2 diabetes adversely affects brain volumes, changes in volume, and cognitive function. RESEARCH DESIGN AND METHODS Regional brain volumes and ischemic lesion volumes in 1,366 women, aged 72–89 years, were measured with structural brain magnetic resonance imaging (MRI). Repeat scans were collected an average of 4.7 years later in 698 women. Cross-sectional differences and changes with time between women with and without diabetes were compared. Relationships that cognitive function test scores had with these measures and diabetes were examined. RESULTS The 145 women with diabetes (10.6%) at the first MRI had smaller total brain volumes (0.6% less; P = 0.05) and smaller gray matter volumes (1.5% less; P = 0.01) but not white matter volumes, both overall and within major lobes. They also had larger ischemic lesion volumes (21.8% greater; P = 0.02), both overall and in gray matter (27.5% greater; P = 0.06), in white matter (18.8% greater; P = 0.02), and across major lobes. Overall, women with diabetes had slightly (nonsignificant) greater loss of total brain volumes (3.02 cc; P = 0.11) and significant increases in total ischemic lesion volumes (9.7% more; P = 0.05) with time relative to those without diabetes. Diabetes was associated with lower scores in global cognitive function and its subdomains. These relative deficits were only partially accounted for by brain volumes and risk factors for cognitive deficits. CONCLUSIONS Diabetes is associated with smaller brain volumes in gray but not white matter and increasing ischemic lesion volumes throughout the brain. These markers are associated with but do not fully account for diabetes-related deficits in cognitive function.

Recovery of hippocampal network connectivity correlates with cognitive improvement in mild alzheimer's disease patients treated with donepezil assessed by resting-state fMRI

To identify the neural correlates of cognitive improvement in mild Alzheimers disease (AD) subjects following 12 weeks of donepezil treatment.

Identification of Hyperactive Intrinsic Amygdala Network Connectivity Associated with Impulsivity in Abstinent Heroin Addicts

Impulsivity is a pathological hallmark of drug addiction. However, little is known about the neuropsychological underpinnings of this impaired impulsive control network on drug addiction. Twenty two abstinent heroin dependent (HD) subjects and 15 cognitively normal (CN) subjects participated in this study. Resting-state functional connectivity MRI was employed to measure abnormalities in the intrinsic amygdala functional connectivity (iAFC) network activity and the Barratt Impulsive Scale, 11th version was used to measure impulsivity. Linear regression analysis was applied to detect the neural constructs underlying impulsivity by correlating iAFC network activity with impulsive scores. In the HD group, higher impulsivity scores and significantly enhanced iAFC network activity were found, especially in bilateral thalamus, right insula, and inferior frontal gyrus. Markedly decreased anticorrelated iAFC network activity was seen in the left precuneus, and even switched to positive correlation pattern in right precuneus, relative to the CN group. The iAFC network strengths in the HD group were positively correlated with impulsivity in the right subcallosal gyrus, insula, thalamus and posterior cingulate cortex, and negatively correlated in left fusiform area. In the CN group, the left pre-somamotor area-amygdala connectivity was positively correlated, and right orbital frontal cortex-amygdala and precuneus-amygdala connectivity were negatively correlated with impulsivity scores. Our study demonstrates different constructs of the impulsive network in HD and CN subjects. Altered iAFC network connectivity in HD subjects may contribute to the loss of impulsive control. This further facilitates our understanding of the neural underpinnings of behavior dysfunction in addiction.

Antidepressant Use, Depressive Symptoms, and Incident Frailty in Women Aged 65 and Older from the Women's Health Initiative Observational Study

To examine the associations between depressive symptoms, antidepressant use, and duration of use with incident frailty 3 years later in nonfrail women aged 65 and older.

Platelet serotonin content correlates inversely with life history of aggression in personality-disordered subjects

The objective of this study was to test the hypothesis that platelet serotonin (5-hydroxytryptamine, 5-HT) content is correlated with measures of aggression in healthy human subjects. Platelet 5-HT content (ng/mg protein) was measured in personality-disordered (PD) and normal control (NC) subjects. Aggression was assessed with the Life History of Aggression (LHA), the Buss-Durkee Hostility Inventory (BDHI), and the Motor Aggression and Research Criteria for Intermittent Explosive Disorder (IED-IR); impulsivity was assessed with the Eysenck Personality Questionnaire II (EPQII) and the Barratt Impulsiveness Scale (BIS-11). LHA Aggression, but not impulsivity, scores showed significant inverse correlations with platelet 5-HT content in all subjects or in PD subjects alone. The findings in PD subjects remained significant after co-varying for race. PD subjects with IED-IR had lower platelet 5-HT content compared with PD subjects who did not have IED-IR, although this finding only approached significance after controlling for race. This study demonstrates an association between reduced platelet 5-HT content and aggression in PD subjects. Similar to other studies of platelet 5-HT markers, these data suggest that platelet 5-HT content may also reflect central 5-HT alterations and may be used as a biological marker in appropriate patient samples.

Cardiovascular Disease and Cognitive Decline in Postmenopausal Women: Results From the Women's Health Initiative Memory Study

Background Data on cardiovascular diseases (CVD) and cognitive decline are conflicting. Our objective was to investigate if CVD is associated with an increased risk for cognitive decline and to examine whether hypertension, diabetes, or adiposity modify the effect of CVD on cognitive functioning. Methods and Results Prospective follow‐up of 6455 cognitively intact, postmenopausal women aged 65 to 79 years old enrolled in the Womens Health Initiative Memory Study (WHIMS). CVD was determined by self‐report. For cognitive decline, we assessed the incidence of mild cognitive impairment (MCI) or probable dementia (PD) via modified mini‐mental state examination (3 MS) score, neurocognitive, and neuropsychiatric examinations. The median follow‐up was 8.4 years. Women with CVD tended to be at increased risk for cognitive decline compared with those free of CVD (hazard ratio [HR], 1.29; 95% CI: 1.00, 1.67). Women with myocardial infarction or other vascular disease were at highest risk (HR, 2.10; 95% CI: 1.40, 3.15 or HR, 1.97; 95% CI: 1.34, 2.87). Angina pectoris was moderately associated with cognitive decline (HR 1.45; 95% CI: 1.05, 2.01) whereas no significant relationships were found for atrial fibrillation or heart failure. Hypertension and diabetes increased the risk for cognitive decline in women without CVD. Diabetes tended to elevate the risk for MCI/PD in women with CVD. No significant trend was seen for adiposity. Conclusions CVD is associated with cognitive decline in elderly postmenopausal women. Hypertension and diabetes, but not adiposity, are associated with a higher risk for cognitive decline. More research is warranted on the potential of CVD prevention for preserving cognitive functioning.

Depression and frailty in later life: a systematic review

Frailty and depression are important issues affecting older adults. Depressive syndrome may be difficult to clinically disambiguate from frailty in advanced old age. Current reviews on the topic include studies with wide methodological variation. This review examined the published literature on cross-sectional and longitudinal associations between frailty and depressive symptomatology with either syndrome as the outcome, moderators of this relationship, construct overlap, and related medical and behavioral interventions. Prevalence of both was reported. A systematic review of studies published from 2000 to 2015 was conducted in PubMed, the Cochrane Database of Systematic Reviews, and PsychInfo. Key search terms were “frailty”, “frail”, “frail elderly”, “depressive”, “depressive disorder”, and “depression”. Participants of included studies were ≥55 years old and community dwelling. Included studies used an explicit biological definition of frailty based on Fried et al’s criteria and a screening measure to identify depressive symptomatology. Fourteen studies met the inclusion/exclusion criteria. The prevalence of depressive symptomatology, frailty, or their co-occurrence was greater than 10% in older adults ≥55 years old, and these rates varied widely, but less in large epidemiological studies of incident frailty. The prospective relationship between depressive symptomatology and increased risk of incident frailty was robust, while the opposite relationship was less conclusive. The presence of comorbidities that interact with depressive symptomatology increased incident frailty risk. Measurement variability of depressive symptomatology and inclusion of older adults who are severely depressed, have cognitive impairment or dementia, or stroke may confound the frailty syndrome with single disease outcomes, accounting for a substantial proportion of shared variance in the syndromes. Further study is needed to identify medical and behavioral interventions for frailty and depressive symptomatology that prevent adverse sequelae such as falls, disability, and premature mortality.

Neural correlates of the interactive relationship between memory deficits and depressive symptoms in nondemented elderly: Resting fMRI study

Prospective studies have shown an association between depressive symptoms and cognitive impairment among older adults. However, the neural correlates of this relationship are poorly understood. Our aim was to examine whether interactive effects of memory deficits and depressive symptoms are present in the memory-associated functional networks, in nondemented elderly subjects. Fifteen subjects with amnestic mild cognitive impairment (aMCI) and 20 age-matched normal (CN) elderly subjects participated in this cross-sectional study. Resting-state functional connectivity MRI (R-fMRI) measured the hippocampal functional connectivity (HFC) alterations between the two groups. Voxelwise linear regression analysis was performed to correlate hippocampal network strength with the Rey Auditory Verbal Learning Test delayed recall and the Geriatric Depression Scale scores, after adjusting for age and group effects. Poorer memory performance was associated with decreased positively correlated HFC connectivity in the specific frontal lobe and default mode network (DMN) structures. Poorer memory performance also was associated with decreased anticorrelated HFC connectivity in the bilateral inferior parietal and right dorsolateral prefrontal cortices. In contrast, greater depressive symptom severity was associated with increased HFC connectivity in several frontal lobes and DMN regions. Depressive symptoms and memory functions had interactive effects on the HFC, in the frontal, temporal, and PCC structures. Our findings suggest that the R-fMRI technique can be used to examine the changes in functional neural networks where memory deficits and depressive symptoms coexist in the geriatric population.