Poor self-rated health is associated with faster cognitive decline and greater small vessel disease in older adults with type 2 diabetes.

OBJECTIVE: Self-rated health (SRH) is a predictor for poor health outcomes and cognition. Older adults with type 2 diabetes mellitus (T2D) have multi-morbidity and greater cognitive impairment. In the present study we investigated the association of SRH with cognitive decline and brain pathology in older adults with T2D. METHODS: Participants (n = 1122) were from the Israel Diabetes and Cognitive Decline study, and SRH was categorised as low (n = 202), moderate (n = 400) or high (n = 520). Cognition was measured by four cognitive domains: episodic memory, executive functions, language, and attention/working memory. Global cognition was the average of the cognitive domains. Statistical models adjusted for sociodemographic, cardiovascular, and clinical variables. In a randomly selected subsample (n = 230) that had magnetic resonance imaging, we examined relationships between baseline SRH and brain characteristics (white matter hyperintensities [WMHs], hippocampal, and total grey matter [GM] volumes). RESULTS: Low SRH was associated with a decline in executive functions, which accelerated over time when compared to high SRH (est = -0.0036; p = <0.001). Compared to high SRH, low SRH was associated with a faster decline in global cognition (est = -0.0024; p = 0.009). Low SRH at baseline was associated with higher volumes of WMHs (est = 9.8420; p < 0.0008). SRH was not associated with other cognitive domains, or with hippocampal and total GM. CONCLUSIONS: Low SRH is associated with cognitive decline in T2D older adults and may serve as a risk assessment. WMHs may represent an underlying mechanism.

Neuropsychiatric Symptom Profile in Alzheimer's Disease and Their Relationship With Functional Decline.

OBJECTIVE: Understanding the course of individual neuropsychiatric symptoms (NPS) and their relationship with function is important for planning targeted interventions for preventing and delaying functional decline. This study aims to disentangle relative contributions of individual NPS on functional decline. METHODS: Longitudinal study of 9,358 well-characterized participants with baseline diagnoses of Mild Cognitive Impairment or AD in the National Alzheimer's Coordinating Center Uniform Data Set. Function was measured using the Functional Assessment Questionnaire (FAQ). Clinician judgment of seven common behavioral symptoms were examined simultaneously: apathy-withdrawal, depressed mood, visual or auditory hallucinations, delusions, disinhibition, irritability, and agitation. RESULTS: Apathy was the most common NPS at baseline (33.7%) and throughout follow-up, endorsed by clinicians in 63.7% of visits. Apathy was the most persistent with 36.7% of participants having clinician-endorsed apathy in ≥50% of their visits. Apathy strongly correlated with faster rate of functional decline. Compared to those who never had apathy, baseline FAQ was worse in those with intermittent or persistent/always apathy (intermittent: estimated coefficient ±SE=1.228±0.210, 95% CI=[0.817, 1.639]; persistent/always: 2.354±0.244 (95% CI=[1.876, 2.832], both p <0.001). Over time, rate of functional decline was faster in those with intermittent and persistent/always apathy (intermittent: 0.454±0.091, 95% CI=[0.276, 0.632]; persistent/always: 0.635±0.102, 95% CI=[0.436, 0.835], both p <0.001). Worse agitation, delusions, and hallucinations also correlated with functional decline, but magnitudes of the estimates were smaller. CONCLUSION: Individual NPS may be sensitive targets for tracking longitudinal change in function. The study raises awareness of the need for more comprehensive assessment of functional decline in AD patients with noncognitive symptoms.

Neuroticism is associated with increase in depression symptoms over time in older adults with type 2 diabetes.

OBJECTIVES: The likelihood of depression symptoms in those with type 2 diabetes (T2D) is high. Psychological risk factors enhancing comorbidity of depression symptoms in T2D are yet to be determined. The present study examines the cross-sectional and longitudinal relationship between personality traits and distinct depression dimensions in older adults with T2D. METHODS: Participants were older adults (age ≥65yeas) with T2D from the Israel Diabetes and Cognitive Decline (IDCD) study (N = 356), with complete data on depression [Geriatric Depression Scale (GDS) - 15 item version] and its dimensions- namely, dysphoric mood, apathy, hopelessness, memory complains and anxiety, and on personality [Big Five Inventory (BFI)]. Logistic and mixed linear regression models examined cross-sectional and longitudinal associations while adjusting for socio-demographics, cognition, cardiovascular and diabetes-related factors. RESULTS: Cross-sectionally, high neuroticism was associated with high scores in total GDS and in all depression-dimensions, except memory complaints. Higher extroversion was associated with lower total GDS and with lower scores on all depression dimensions, except anxiety. High levels of neuroticism were associated with increase in total number of depression symptoms over time. CONCLUSIONS: In older adults with T2D, neuroticism and extroversion are associated with most depression dimensions suggesting that these traits relate to a global depression symptomatology rather than to any specific dimension or phenomenology. High neuroticism was associated with increase in depression symptoms over time, highlighting its role in the development of depression symptoms in older adults with T2D.

Increase in Number of Depression Symptoms Over Time is Related to Worse Cognitive Outcomes in Older Adults With Type 2 Diabetes.

OBJECTIVE: Older adults with type 2 diabetes (T2D) are at increased risk for depression, cognitive decline, and dementia compared to those without T2D. Little is known about the association of simultaneous changes in depression symptoms and cognitive decline over time. METHODS: Subjects (n=1021; mean age 71.6 [SD=4.6]; 41.2% female) were initially cognitively normal participants of the Israel Diabetes and Cognitive Decline study who underwent evaluations of depression and cognition approximately every 18 months. Cognitive tests were summarized into four cognitive domains: episodic memory, attention/working memory, executive functions, and semantic categorization. The average of the z-scores of the four domains defined global cognition. Depression symptoms were assessed using the Geriatric Depression Scale, 15-item version. We fit a random coefficients model of changes in depression and in cognitive functions, adjusting for baseline sociodemographic and cardiovascular variables. RESULTS: Higher number of depression symptoms at baseline was significantly associated with lower baseline cognitive scores in global cognition (estimate = -0.1175, SE = 0.021, DF = 1,014, t = -5.59; p < 0.001), executive functions (estimate = -0.186, SE = 0.036, DF = 1,013, t = -5.15; p = <0.001), semantic categorization (estimate = -0.155, SE = 0.029, DF = 1,008, t = -5.3; p < 0.001), and episodic memory (estimate = -0.08165, SE = 0.027, DF = 1,035, t = -2.92; p = 0.0036), but not with rate of decline in any cognitive domain. During follow-up, a larger increase in number of depression symptoms, was associated with worse cognitive outcomes in global cognition (estimate = -0.1053, SE = 0.027, DF = 1,612, t = -3.77; p = 0.0002), semantic categorization (estimate = -0.123, SE = 0.036, DF = 1,583, t = -3.36; p = 0.0008), and in episodic memory (estimate = -0.165, SE = 0.055, DF = 1,622, t = -3.02; p = 0.003), but the size of this effect was constant over time. CONCLUSION: In elderly with T2D, increase in depression symptoms over time is associated with parallel cognitive decline, indicating that the natural course of the two conditions progresses concurrently and suggesting common underlying mechanisms".

Trajectories of depression symptoms over time differ by APOE4 genotype in older adults with type 2 diabetes.

OBJECTIVES: The APOE-ε4 genotype has been associated with old-age depression, but this relationship has been rarely investigated in type 2 diabetes (T2D) older adults, who are at significantly increased risk for depression, a major contributor to T2D complications. We examined whether trajectories of depression symptoms over time differ by APOE-ε4 genotype in older adults with T2D. METHODS: Participants (n = 754 [13.1% APOE-ε4 carrier]s) were from the longitudinal Israel Diabetes and Cognitive Decline (IDCD) study. They were initially cognitively normal and underwent evaluations of depression approximately every 18 months using the 15-item version of the Geriatric Depression Scale (GDS) and the depression subscale of the Neuropsychiatric Inventory (NPI). APOE was defined as a dichotomy of ε4 carriers and non-carriers. We used Hierarchical Linear Mixed Models (HLMM) that modeled the effects of APOE status on repeated GDS and NPI-depression scores in an unadjusted model (Model 1), adjusting for demographic factors (Model 2) and additionally adjusting for cardiovascular factors and global cognition (Model 3). RESULTS: Participants' mean age was 71.37 (SD = 4.5); 38.2% female. In comparison to non-carriers, APOE-ε4 carriers had lower mean GDS scores (ß = -0.46, p = 0.018) and lower NPI-depression scores (ß = -0.170, p = 0.038) throughout all study follow period. The groups did not differ in the slope of change over time in GDS (ß = -0.005, p = 0.252) or NPI-depression (ß = -0.001, p = 0.994) scores. Additional adjustment for cardiovascular factors and global cognition did not alter these results. CONCLUSIONS: In older adults with T2D, APOE-ε4 carriers have less depressive symptoms in successive measurements suggesting they may be less susceptible to depression.

Depression is more strongly associated with cognition in elderly women than men with type 2 diabetes.

Depression and cognitive impairment are highly prevalent in type 2 diabetes (T2D), yet little is known about how their relationship varies by sex. We examined this question in a large T2D sample (N = 897) of non-demented elderly (≥ 65) participating in the Israel Diabetes and Cognitive Decline (IDCD) Study. Cognition was evaluated by a comprehensive neuropsychological battery and depressive symptoms were assessed by the Geriatric Depression Scale (GDS). The results showed that in all but the executive function domain, the association of depressive symptoms with poorer cognitive function was stronger in women than men, with a significant interaction for language/semantic categorization and missed significance for episodic memory. When defining clinical depression as GDS of ≥6, women with depression had significantly poorer language/semantic categorization, episodic memory, and overall cognitive function. Inclusion of antidepressants in the model did not alter substantively the associations. Our results suggest that depressed T2D women may have poorer cognitive performance, highlighting the significance of sex-specific personalized management of depression in elderly diabetics.

Prazosin during threat discrimination boosts memory of the safe stimulus.

The α-1 adrenoreceptor antagonist prazosin has shown promise in the treatment of post-traumatic stress disorder (PTSD) symptoms, but its mechanisms are not well understood. Here we administered prazosin or placebo prior to threat conditioning (day 1) and tested subsequent extinction (day 2) and reextinction (day 3) in healthy human participants. Prazosin did not affect threat conditioning but augmented stimulus discrimination during extinction and reextinction, via lower responding to the safe stimulus. These results suggest that prazosin during threat acquisition may have influenced encoding or consolidation of safety processing in particular, subsequently leading to enhanced discrimination between the safe and threatening stimuli.

Cerebrospinal fluid neuropeptide Y levels in major depression and reported childhood trauma.

BACKGROUND: Neuropeptide Y (NPY) may enhance resilience to chronic stress. Low brain NPY reported in major depression may normalize in response to antidepressants. METHODS: In this study, we examined the relationship of reported childhood trauma to cerebrospinal fluid (CSF) NPY-like immunoreactivity (NPY-LI) in 61 medication-free major depressive disorder (MDD) patients and 20 matched healthy volunteers. RESULTS: Higher CSF NPY-LI was found in MDD compared to the healthy volunteer group (p = 0.01). A positive correlation of CSF NPY-LI with more adverse childhood trauma (p = 0.001) may be indicative of an intact but insufficient NPY-related stress response. CONCLUSIONS: We hypothesize that differences in published results may be explained by the existence of two groups of MDD in terms of CSF NPY levels: MDD with low CSF NPY prior to stress or in response to stress, and those with robust NPY responses to stress. Future studies should confirm the two groups and seek the molecular mechanism for their differences.

Effects of ketamine on explicit and implicit suicidal cognition: a randomized controlled trial in treatment-resistant depression.

BACKGROUND: Preliminary evidence suggests intravenous ketamine has rapid effects on suicidal cognition, making it an attractive candidate for depressed patients at imminent risk of suicide. In the first randomized controlled trial of ketamine using an anesthetic control condition, we tested ketamine's acute effects on explicit suicidal cognition and a performance-based index of implicit suicidal cognition (Implicit Association Test; IAT) previously linked to suicidal behavior. METHOD: Symptomatic patients with treatment-resistant unipolar major depression (inadequate response to ≥3 antidepressants) were assessed using a composite index of explicit suicidal ideation (Beck Scale for Suicidal Ideation, Montgomery-Asberg Rating Scale suicide item, Quick Inventory of Depressive Symptoms suicide item) and the IAT to assess suicidality implicitly. Measures were taken at baseline and 24 hr following a single subanesthetic dose of ketamine (n = 36) or midazolam (n = 21), a psychoactive placebo agent selected for its similar, rapid anesthetic effects. Twenty four hours postinfusion, explicit suicidal cognition was significantly reduced in the ketamine but not the midazolam group. RESULTS: Fifty three percent of ketamine-treated patients scored zero on all three explicit suicide measures at 24 hr, compared with 24% of the midazolam group (χ(2) = 4.6; P = .03). Implicit associations between self- and escape-related words were reduced following ketamine (P = .01; d = .58) but not midazolam (P = .68; d = .09). Ketamine-specific decreases in explicit suicidal cognition were largest in patients with elevated suicidal cognition at baseline, and were mediated by decreases in nonsuicide-related depressive symptoms. CONCLUSIONS: Intravenous ketamine produces rapid reductions in suicidal cognition over and above active placebo. Further study is warranted to test ketamine's antisuicidal effects in higher-risk samples.

Speech markers of depression dimensions across cognitive status.

Introduction: Depression and its components significantly impact dementia prediction and severity, necessitating reliable objective measures for quantification. Methods: We investigated associations between emotion-based speech measures (valence, arousal, and dominance) during picture descriptions and depression dimensions derived from the geriatric depression scale (GDS, dysphoria, withdrawal-apathy-vigor (WAV), anxiety, hopelessness, and subjective memory complaint). Results: Higher WAV was associated with more negative valence (estimate = -0.133, p = 0.030). While interactions of apolipoprotein E (APOE) 4 status with depression dimensions on emotional valence did not reach significance, there was a trend for more negative valence with higher dysphoria in those with at least one APOE4 allele (estimate = -0.404, p = 0.0846). Associations were similar irrespective of dementia severity. Discussion: Our study underscores the potential utility of speech biomarkers in characterizing depression dimensions. In future research, using emotionally charged stimuli may enhance emotional measure elicitation. The role of APOE on the interaction of speech markers and depression dimensions warrants further exploration with greater sample sizes. Highlights: Participants reporting higher apathy used more negative words to describe a neutral picture.Those with higher dysphoria and at least one APOE4 allele also tended to use more negative words.Our results suggest the potential use of speech biomarkers in characterizing depression dimensions.

Decrease in Gait Speed Over Time Is Associated With Increase in Number of Depression Symptoms in Older Adults With Type 2 Diabetes.

BACKGROUND: We examined the cross-sectional and longitudinal relationships of motor functions with depression in older adults with type 2 diabetes (T2D). METHODS: Participants (n = 984) were from the longitudinal Israel Diabetes and Cognitive Decline (IDCD) study. They were initially cognitively normal and underwent evaluations of motor functions (grip strength and gait speed) and of depression (using the 15-item version of the Geriatric Depression Scale [GDS]) approximately every 18 months. We applied Hierarchical Linear Mixed Models (HLMM) to investigate the associations between motor functions and depression adjusting for sociodemographic, cardiovascular factors, overall cognitive score, and subjective report of exhaustion. RESULTS: Participants' baseline characteristics were 72 (±5) years of age (59.6% males), 13 (±4) years of education, Mini-Mental Status Exam (MMSE) score of 28.01 (±1.78), and a GDS score of (2 ± 2.00), consistent with normal cognitive status and lack of major affective symptomatology. Slower gait speed at baseline was associated with higher GDS scores (p = .001) and with their increase over time (p = .049). A decrease in walking speed from baseline was associated with an increase in GDS scores (p = .015). Lower grip strength at baseline was associated with higher GDS scores (p = .002), but not with trajectories in GDS scores over time. A faster decrease in grip strength from baseline was associated with a faster increase in GDS scores (p = .022). CONCLUSIONS: Both gait speed and grip strength are cross-sectionally associated with depression. However, only gait speed and its decrease over time can potentially be used to predict incident depression symptoms, thus facilitating the introduction of depression prevention strategies.

Specific depression dimensions are associated with a faster rate of cognitive decline in older adults.

Introduction: Understanding the relationship between different depression presentations and cognitive outcome may elucidate high-risk sub-groups for cognitive decline. Methods: In this study we utilized longitudinal data from the National Alzheimer's Coordinating Center (NACC) on 16,743 initially not demented older adults followed every 12 months for an average of 5 years. Depression dimensions were defined based on the 15-item Geriatric Depression Scale (GDS-15), that is, dysphoric mood, Withdrawal-Apathy-Vigor (WAV), anxiety, hopelessness, and subjective memory complaint (SMC). Results: After adjustment for sociodemographic and clinical covariates, SMC and hopelessness were associated with faster decline in global cognition and all cognitive domains and WAV with decline executive function. Dysphoric mood and anxiety were not associated with a faster cognitive decline in any of the cognitive domains. Discussion: Different depression dimensions had different associations with the rate of cognitive decline, suggesting distinct pathophysiology and the need for more targeted interventions.

Prevalent, persistent, and impairing: Longitudinal course and impact of apathy in Alzheimer's disease.

INTRODUCTION: Understanding of the natural history of apathy and its impact on patient function is limited. This study examines, in a large, national sample of Alzheimer's disease (AD) patients with long follow-ups: (1) prevalence, incidence, and persistence of apathy, and (2) impact of apathy on function across dementia severity. METHODS: A longitudinal study of 9823 well-characterized AD patients in the National Alzheimer's Coordinating Center Uniform Data Set. RESULTS: Apathy was highly prevalent across disease severity with cumulative prevalence of 48%, 74%, and 82% in Clinical Dementia Rating (CDR) 0.5, 1.0, and 2.0, respectively. Persistence of apathy from clinician judgment varied from visit to visit at earlier disease stages but remained high at moderate dementia. Independent of cognition, persistent apathy was strongly associated with accelerated rate of functional decline. DISCUSSION: Findings point to important targets for the treatment and management of apathy, include functional outcomes, and study designs that account for variable persistence of the apathy syndrome.

Specific Dimensions of Depression Have Different Associations With Cognitive Decline in Older Adults With Type 2 Diabetes.

OBJECTIVE: Depression is highly frequent in older adults with type 2 diabetes and is associated with cognitive impairment, yet little is known about how various depression dimensions differentially affect cognition. We investigated longitudinal associations of specific depression dimensions with cognitive decline. RESEARCH DESIGN AND METHODS: Participants (N = 1,002) were from the Israel Diabetes and Cognitive Decline study, were ≥65 years of age, had type 2 diabetes, and were not experiencing dementia at baseline. Participants underwent a comprehensive neuropsychological battery at baseline and every 18 months thereafter, including domains of episodic memory, attention/working memory, semantic categorization/language, and executive function, and Z-scores of each domain were averaged and further normalized to calculate global cognition. Depression items from the 15-item Geriatric Depression Scale were measured at each visit and subcategorized into five dimensions: dysphoric mood, withdrawal-apathy-vigor (entitled apathy), anxiety, hopelessness, and memory complaint. Random coefficients models examined the association of depression dimensions with baseline and longitudinal cognitive functioning, adjusting for sociodemographics and baseline characteristics, including cardiovascular risk factors, physical activity, and use of diabetes medications. RESULTS: In the fully adjusted model at baseline, all dimensions of depression, except for anxiety, were associated with some aspect of cognition (P values from 0.01 to <0.001). Longitudinally, greater apathy scores were associated with faster decline in executive function (P = 0.004), a result that withstood adjustment for multiple comparisons. Associations of other depression dimensions with cognitive decline were not significant (P > 0.01). CONCLUSIONS: Apathy was associated with a faster cognitive decline in executive function. These findings highlight the heterogeneity of depression as a clinical construct rather than as a single entity and point to apathy as a specific risk factor for cognitive decline among older adults with type 2 diabetes.

Vitamin E Intake Is Associated with Lower Brain Volume in Haptoglobin 1-1 Elderly with Type 2 Diabetes.

BACKGROUNDS: The efficacy of vitamin E in prevention of diabetes-related complications differs by Haptoglobin (Hp) genotype. OBJECTIVE: To examine the role of Hp genotype in the relationship of vitamin E intake with brain volume in cognitively normal elderly patients with type 2 diabetes. METHODS: Brain volumes for the superior, middle, and inferior frontal gyri and for the middle temporal gyrus were generated from structural T1 MRI in 181 study participants (Hp 1-1: n = 24, Hp 2-1: n = 77, Hp 2-2: n = 80). Daily vitamin E intake was assessed using the Food Frequency Questionnaire. Analyses of covariance, controlling for demographic and cardiovascular variables was used to evaluate whether the association of daily vitamin E intake with brain volume was modified by Hp genotype. RESULTS: Average age was 70.8 (SD = 4.2) with 40% females, and mean Mini-Mental State Examination score of 28.17 (SD = 1.90). A significant interaction was found between vitamin E intake and Hp genotype in inferior frontal gyrus' volume; p = 0.0108. For every 1 microgram increase in vitamin E intake, the volume of the inferior frontal gyrus decreased by 0.955% for Hp 1-1 (p = 0.0348), increased by 0.429% for Hp 2-1 (p = 0.0457), and by 0.077% for Hp 2-2 (p = 0.6318). There were no significant interactions between vitamin E intake and Hp genotype for the middle (p = 0.6011) and superior (p = 0.2025) frontal gyri or for the middle temporal gyrus (p = 0.503). CONCLUSIONS: The effect of dietary vitamin E on the brain may differ by Hp genotype. Studies examining the impact of vitamin E on brain-related outcomes should consider Hp genotype.

Lithium continuation therapy following ketamine in patients with treatment resistant unipolar depression: a randomized controlled trial.

The N-methyl-D-aspartate (NMDA) receptor antagonist ketamine is associated with rapid but transient antidepressant effects in patients with treatment resistant unipolar depression (TRD). Based on work suggesting that ketamine and lithium may share overlapping mechanisms of action, we tested lithium compared to placebo as a continuation strategy following ketamine in subjects with TRD. Participants who met all eligibility criteria and showed at least an initial partial response to a single intravenous infusion of ketamine 0.5 mg/kg were randomized under double-blind conditions to lithium or matching placebo before receiving an additional three infusions of ketamine. Subsequent to the ketamine treatments, participants remained on lithium or placebo during a double-blind continuation phase. The primary study outcome was depression severity as measured by the Montgomery-Åsberg Depression Rating Scale compared between the two groups at Study Day 28, which occurred ~2 weeks following the final ketamine of four infusions. Forty-seven participants with TRD were enrolled in the study and underwent an initial ketamine infusion, of whom 34 participants were deemed to have at least a partial antidepressant response and were eligible for randomization. Comparison between treatment with daily oral lithium (n = 18) or matching placebo (n = 16) at the primary outcome showed no difference in depression severity between groups (t32 = 0.11, p = 0.91, 95% CI [-7.87, 8.76]). There was no difference between lithium and placebo in continuing the acute antidepressant response to ketamine. The identification of a safe and effective strategy for preventing depression relapse following an acute course of ketamine treatment remains an important goal for future studies.

The Association of Depressive Symptoms With Brain Volume Is Stronger Among Diabetic Elderly Carriers of the Haptoglobin 1-1 Genotype Compared to Non-carriers.

Aim: Depression is highly prevalent in type 2 diabetes and is associated with lower adherence to medical treatments, worse glycemic control, and increased risk for diabetes-related complications. The mechanisms underlying depression in type 2 diabetes are unclear. The haptoglobin (Hp) genotype is associated with type 2 diabetes related complications including increased risk for cerebrovascular pathology and worse cognitive performance. Its relationship with depression is unknown. We investigated the role of Hp genotype on the association of depression with brain and white matter hyperintensities (WMH) volumes. Methods: Depressive symptoms (measured with the 15-item Geriatric Depression Scale), brain MRI, and Hp genotypes, were examined in elderly subjects with type 2 diabetes [29 (13.8%) Hp 1-1 carriers and 181 (86.2%) non-carriers]. The interaction of Hp genotype with number of depressive symptoms on regional brain measures was assessed using regression analyses. Results: The significant interactions were such that in Hp 1-1 carriers but not in non-carriers, number of depressive symptoms was associated with overall frontal cortex (p = 0.01) and WMH (p = 0.04) volumes but not with middle temporal gyrus volume (p = 0.43). Conclusions: These results suggest that subjects with type 2 diabetes carrying the Hp 1-1 genotype may have higher susceptibility to depression in the context of white matter damage and frontal lobe atrophy. The mechanisms underlying depression in diabetes may differ by Hp genotype.