Gender-stratified analyses reveal longitudinal associations between social support and cognitive decline in older men.

Objectives: Research has extensively examined the relationship between social support and health outcomes in older adults. Little is known, however, about the longitudinal associations between distinct dimensions of perceived social support and incident cognitive decline. The current longitudinal study examined whether dimensions of perceived social support were associated with increased risk of cognitive decline, and if the relationship differed by gender. Methods: 493 community-residing non-demented older adults were assessed for baseline social support via the Medical Outcomes Study-Social Support Survey (MOS-SSS). Incident cognitive impairment was determined using a 1 standard deviation below age and education adjusted total score on the Repeatable Battery for the Assessment of Neuropsychological Status Cox proportional-hazard models were used to analyze incident risk of cognitive impairment. Results: Higher perceived support, overall and in specific domains, at baseline was associated with increased risk of incident cognitive impairment. Further gender-stratified analyses revealed that higher perceived support at baseline was associated with increased risk of incident cognitive impairment only among males. Conclusion: Contrary to previous research, results from this longitudinal study suggest that perceived support might be an important risk factor for cognitive decline, notably in males, and should be integrated into multifactorial risk assessment and intervention procedures.

Guilt after placement questionnaire: a new instrument to assess caregiver emotional functioning following nursing home placement.

OBJECTIVE: Guilt is a core feature of dementia caregivers' experiences following placement. This study describes and validates a new assessment tool for monitoring caregiver adjustment after placement. METHODS: Forty-six items addressing ambivalence and guilt about placement were tested with 170 dementia caregivers (M age = 56.79, SD = 13.19; 69.4% female; 54.7% adult child). RESULTS: Using principal axis factor analysis, 10 items were retained that showed acceptable internal consistency (Cronbach's alpha of 0.92). Construct validity was established in a subset of the sample (n = 53) with measures of depression (r = 0.53), burden (r = 0.48), conflict with staff (r = 0.47), and well-being (r = -0.30). CONCLUSIONS: This scale may be used to identify caregivers at risk for adjustment problems following placement and to monitor adjustment over time.

The Modified Telephone-Administered Minnesota Cognitive Acuity Screen for Mild Cognitive Impairment.

OBJECTIVE: This study aimed to compare the sensitivity and specificity of a modified version of the Minnesota Cognitive Acuity Screen (MCAS-m), by adding learning and recognition memory components, to the original version MCAS to distinguish amnestic mild cognitive impairment (aMCI) from healthy controls (HCs). METHODS/DESIGN: A total of 30 individuals with aMCI and 30 HCs underwent neuropsychological testing, neurologic examination, laboratory, and brain imaging tests. Once diagnosis was confirmed, participants completed the MCAS and MCAS-m in counterbalanced order. RESULTS: The average administration time was 12.6 minutes for the MCAS and 13.5 minutes for the MCAS-m. Receiver operating characteristic curve analyses showed that the MCAS-m demonstrated 97% sensitivity and 97% specificity for distinguishing between aMCI and HC versus 97% and 87%, respectively, for the original MCAS in this sample. CONCLUSIONS: Both the MCAS and the MCAS-m were highly sensitive when distinguishing between normal cognition and aMCI; however, the MCAS-m demonstrated a 10% increase in specificity compared to the original version. Improved specificity is particularly relevant to screening in larger community samples with lower base rates of MCI than clinic populations. This modified screening measure presents a brief and cost-effective tool for identifying MCI. Given the risk of progression from aMCI to Alzheimer disease dementia (AD), the MCAS-m represents a modest improvement in telephone-administered methods for the early detection of AD.

Gender effects on components of burden and depression among dementia caregivers.

OBJECTIVE: Previous literature has examined burden and depression predominately as unitary constructs in relation to dementia caregiving. No studies thus far have examined gender differences in the specific components of burden and depression in dementia caregivers. The current study examined whether empirically validated dimensions of caregiver burden differed by gender for dementia caregivers. METHODS: The sample consisted of 211 dementia caregivers enrolled in a longitudinal intervention study. Only baseline functioning was evaluated in this study. Levels of burden were assessed using the Zarit Burden Interview (ZBI), and levels of depression were assessed using the Center for Epidemiologic Studies Depression Scale (CES-D). RESULTS: Factor analysis revealed three facets of burden: impact of caregiving on the caregivers' lives, guilt, and frustration/embarrassment, and four facets of depression: depressed affect, somatic activity, positive affect, and interpersonal feelings. Overall burden (p < .001) and impact of caregiving on the caregivers' life (p < .001) were significantly higher in females. Overall levels of depression (p = .018), somatic and retarded activity (p = .018), depressed affect (p = .005), and positive affect (p = .012) were significantly higher in females. CONCLUSIONS: Findings suggest that distressed male and female dementia caregivers experience caregiving differently. Results from this study could be used to identify gender-specific interventions related to subtypes of burden and depression to optimize quality of life for caregivers.

The differential relationships of dimensions of perceived social support with cognitive function among older adults.

OBJECTIVES: Research has extensively examined the relationship of social support and cognition. Theories on social support suggest that it is a multidimensional construct including perceptions, actual assistance, and level of integration into a social network. Little is known, however, about the differential associations between distinct dimensions of perceived social support and cognition. This study examined whether four empirically validated dimensions of perceived social support were differentially related to cognitive function in aging, and whether this association was moderated by gender. METHODS: The sample included 355 community-residing older adults (mean age = 77 years; %female = 55) enrolled in a longitudinal cohort study. Social support was assessed using the Medical Outcomes Study-Social Support Survey. Cognition was assessed using the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS). RESULTS: Principal component analysis yielded four factors capturing different dimensions of social support: emotional/informational support, positive social interaction, tangible support, and affectionate support. Linear regression analyses revealed that both perceived emotional/informational support (beta = 1.41, p = 0.03; 95% Confidence Interval (CI) = .156-2.669) and positive social interaction (beta = 1.71, p = 0.01; 95% CI = .428-2.988) were significantly associated with RBANS total index score. Further analyses revealed that gender moderated the relationship between emotional/informational support (beta = 1.266, p = 0.04), demonstrating that higher levels of perceived emotional support were associated with higher index scores in females but not in males. DISCUSSION: The associations between perceived emotional/informational support and positive social interaction suggest that social engagement may be an important target for intervention procedures for individuals at risk of cognitive decline and dementia.

Increased ventricular lactate in chronic fatigue syndrome. III. Relationships to cortical glutathione and clinical symptoms implicate oxidative stress in disorder pathophysiology.

Chronic fatigue syndrome (CFS) is a complex illness, which is often misdiagnosed as a psychiatric illness. In two previous reports, using (1)H MRSI, we found significantly higher levels of ventricular cerebrospinal fluid (CSF) lactate in patients with CFS relative to those with generalized anxiety disorder and healthy volunteers (HV), but not relative to those with major depressive disorder (MDD). In this third independent cross-sectional neuroimaging study, we investigated a pathophysiological model which postulated that elevations of CSF lactate in patients with CFS might be caused by increased oxidative stress, cerebral hypoperfusion and/or secondary mitochondrial dysfunction. Fifteen patients with CFS, 15 with MDD and 13 HVs were studied using the following modalities: (i) (1)H MRSI to measure CSF lactate; (ii) single-voxel (1)H MRS to measure levels of cortical glutathione (GSH) as a marker of antioxidant capacity; (iii) arterial spin labeling (ASL) MRI to measure regional cerebral blood flow (rCBF); and (iv) (31)P MRSI to measure brain high-energy phosphates as objective indices of mitochondrial dysfunction. We found elevated ventricular lactate and decreased GSH in patients with CFS and MDD relative to HVs. GSH did not differ significantly between the two patient groups. In addition, we found lower rCBF in the left anterior cingulate cortex and the right lingual gyrus in patients with CFS relative to HVs, but rCBF did not differ between those with CFS and MDD. We found no differences between the three groups in terms of any high-energy phosphate metabolites. In exploratory correlation analyses, we found that levels of ventricular lactate and cortical GSH were inversely correlated, and significantly associated with several key indices of physical health and disability. Collectively, the results of this third independent study support a pathophysiological model of CFS in which increased oxidative stress may play a key role in CFS etiopathophysiology.

Anticholinergic/Sedative Drug Burden and Subjective Cognitive Decline in Older Adults at Risk of Alzheimer's Disease.

BACKGROUND: Anticholinergic/sedative drug use, measured by the Drug Burden Index (DBI), has been linked to cognitive impairment in older adults. Subjective cognitive decline (SCD) may be among the first symptoms patients with Alzheimer's disease (AD) experience. We examined whether DBI values are associated with SCD in older adults at risk of AD. We hypothesized that increased DBI would be associated with greater SCD at older ages. METHOD: Two-hundred-six community-dwelling, English-speaking adults (age = 65 ± 9 years) at risk of AD (42% apolipoprotein ε4 carriers; 78% with AD family history) were administered a single question to ascertain SCD: "Do you feel like your memory is becoming worse?" Response options were "No"; "Yes, but this does not worry me"; and "Yes, this worries me." DBI values were derived from self-reported medication regimens using older adult dosing recommendations. Adjusting for relevant covariates (comorbidities and polypharmacy), we examined independent effects of age and DBI on SCD, as well as the moderating effect of age on the DBI-SCD association at mean ± 1 SD of age. RESULTS: Both SCD and anticholinergic/sedative drug burden were prevalent. Greater drug burden was predictive of SCD severity, but age alone was not. A significant DBI*Age interaction emerged with greater drug burden corresponding to more severe SCD among individuals age 65 and older. CONCLUSION: Anticholinergic/sedative drug exposure was associated with greater SCD in adults 65 and older at risk for AD. Longitudinal research is needed to understand if this relationship is a pre-clinical marker of neurodegenerative disease and predictive of future cognitive decline.

Functional connectivity associated with social networks in older adults: A resting-state fMRI study.

Poor social networks and decreased levels of social support are associated with worse mood, health, and cognition in younger and older adults. Yet, we know very little about the brain substrates associated with social networks and social support, particularly in older adults. This study examined functional brain substrates associated with social networks using the Social Network Index (SNI) and resting-state functional magnetic resonance imaging (fMRI). Resting-state fMRI data from 28 non-demented older adults were analyzed with independent components analyses. As expected, four established resting-state networks-previously linked to motor, vision, speech, and other language functions-correlated with the quality (SNI-1: total number of high-contact roles of a respondent) and quantity (SNI-2: total number of individuals in a respondent's social network) of social networks: a sensorimotor, a visual, a vestibular/insular, and a left frontoparietal network. Moreover, SNI-1 was associated with greater functional connectivity in the lateral prefrontal regions of the left frontoparietal network, while SNI-2 was associated with greater functional connectivity in the medial prefrontal regions of this network. Thus, lateral prefrontal regions may be particularly linked to the quality of social networks while medial prefrontal regions may be particularly linked to the quantity of social networks.

Neural correlates of obstacle negotiation in older adults: An fNIRS study.

Older adults are less efficient at avoiding obstacles compared to young adults, especially under attention-demanding conditions. Using functional near-infrared-spectroscopy (fNIRS), recent studies implicated the prefrontal cortex (PFC) in cognitive control of locomotion, notably under dual-task walking conditions. The neural substrates underlying Obstacle Negotiation (ON), however, have not been established. The current study determined the role of the PFC in ON during walking in seniors. Non-demented older adults (n=90; mean age=78.1±5.5years; %female=51) underwent fNIRS acquisition to assess changes in hemodynamic activity in the PFC during normal-walk [NW] and walk-while-talk [WWT] conditions with and without obstacles. Obstacles were presented as red elliptical shapes using advanced laser technology, which resemble potholes. Linear mixed effects models were used to determine differences in oxygenated hemoglobin (HbO2) levels among the four task conditions. The presence of slow gait, a risk factor for dementia and falls, served as a predictor hypothesized to moderate the effect of obstacles on PFC HbO2 levels. PFC HbO2 levels were significantly higher in WWT compared to NW (p<0.001) irrespective of ON. Slow gait moderated the effect of obstacles on HbO2 levels across task conditions. Specifically, compared to participants with normal gait, PFC HbO2 levels were significantly increased in ON-NW relative to NW (p=0.017) and ON-WWT relative to WWT (p<0.001) among individuals with slow gait. Consistent with Compensatory Reallocation, ON required greater PFC involvement among individuals with mobility limitations.

Rapid and longer-term antidepressant effects of repeated ketamine infusions in treatment-resistant major depression.

BACKGROUND: Ketamine is reported to have rapid antidepressant effects; however, there is limited understanding of the time-course of ketamine effects beyond a single infusion. A previous report including 10 participants with treatment-resistant major depression (TRD) found that six ketamine infusions resulted in a sustained antidepressant effect. In the current report, we examined the pattern and durability of antidepressant effects of repeated ketamine infusions in a larger sample, inclusive of the original. METHODS: Participants with TRD (n = 24) underwent a washout of antidepressant medication followed by a series of up to six IV infusions of ketamine (.5 mg/kg) administered open-label three times weekly over a 12-day period. Participants meeting response criteria were monitored for relapse for up to 83 days from the last infusion. RESULTS: The overall response rate at study end was 70.8%. There was a large mean decrease in Montgomery-Åsberg Depression Rating Scale score at 2 hours after the first ketamine infusion (18.9 ± 6.6, p < .001), and this decrease was largely sustained for the duration of the infusion period. Response at study end was strongly predicted by response at 4 hours (94% sensitive, 71% specific). Among responders, median time to relapse after the last ketamine infusion was 18 days. CONCLUSIONS: Ketamine was associated with a rapid antidepressant effect in TRD that was predictive of a sustained effect. Future controlled studies will be required to identify strategies to maintain an antidepressant response among patients who benefit from a course of ketamine.

Antidepressant efficacy of ketamine in treatment-resistant major depression: a two-site randomized controlled trial.

OBJECTIVE: Ketamine, a glutamate N-methyl-d-aspartate (NMDA) receptor antagonist, has shown rapid antidepressant effects, but small study groups and inadequate control conditions in prior studies have precluded a definitive conclusion. The authors evaluated the rapid antidepressant efficacy of ketamine in a large group of patients with treatment-resistant major depression. METHOD: This was a two-site, parallel-arm, randomized controlled trial of a single infusion of ketamine compared to an active placebo control condition, the anesthetic midazolam. Patients with treatment-resistant major depression experiencing a major depressive episode were randomly assigned under double-blind conditions to receive a single intravenous infusion of ketamine or midazolam in a 2:1 ratio (N=73). The primary outcome was change in depression severity 24 hours after drug administration, as assessed by the Montgomery-Åsberg Depression Rating Scale (MADRS). RESULTS: The ketamine group had greater improvement in the MADRS score than the midazolam group 24 hours after treatment. After adjustment for baseline scores and site, the MADRS score was lower in the ketamine group than in the midazolam group by 7.95 points (95% confidence interval [CI], 3.20 to 12.71). The likelihood of response at 24 hours was greater with ketamine than with midazolam (odds ratio, 2.18; 95% CI, 1.21 to 4.14), with response rates of 64% and 28%, respectively. CONCLUSIONS: Ketamine demonstrated rapid antidepressant effects in an optimized study design, further supporting NMDA receptor modulation as a novel mechanism for accelerated improvement in severe and chronic forms of depression. More information on response durability and safety is required before implementation in clinical practice.