A Randomized Controlled Trial of Tai Chi Chih or Health Education for Geriatric Depression.

OBJECTIVES: Geriatric depression is difficult to treat and frequently accompanied by treatment resistance, suicidal ideations and polypharmacy. New adjunctive mind-body treatment strategies can improve clinical outcomes in geriatric depression and reduce risk for side-effects of pharmacological treatments. METHODS: We conducted a 3-month randomized controlled trial to assess the efficacy and tolerability of combining Tai Chi Chih (TCC) or Health Education and Wellness training (HEW) with the stable standard antidepressant treatment on mood and cognitive functioning in depressed older adults (NCT02460666). Primary outcome was change in depression as assessed by the Hamilton Rating Scale for Depression (HAM-D) post-treatment. Remission was defined as HAM-D ≤ 6; naturalistic follow-up continued for 6 months. We also assessed psychological resilience, health-related quality of life and cognition. RESULTS: Of the 178 randomized participants, 125 completed the 3-month assessment and 117 completed the 6-month assessment. Dropout and tolerability did not differ between groups. Remission rate within TCC was 35.5% and 33.3%, compared to 27.0% and 45.8% in HEW, at 3 and 6 months respectively (χ2(1) = 1.0, p = 0.3; χ2(1) = 1.9, p =0.2). Both groups improved significantly on the HAM-D at 3 and 6 months. TCC demonstrated a greater improvement in general health compared to HEW. CONCLUSIONS: Both TCC and HEW combined with a standard antidepressant treatment improved symptoms of depression in older adults. While TCC was superior to HEW in improving general health, we did not find group differences in improvement in mood and cognition.

The Effect of Memory Training on Memory Control Beliefs in Older Adults with Subjective Memory Complaints.

Objective: To study whether memory control beliefs predict response to memory training, or change as a result of participating in memory training. Methods: Eighty community based participants with subjective memory complaints Community-based study at UCLA were randomized to one of three conditions: Memory Training, the program consisted of weekly 120-minute classes featuring instruction in three specific strategies: Method of Loci; Chunking Technique; and Face-Name Association, Health Education or Wait-List over seven weeks. All participants underwent pre- and 1-week post-intervention follow-up memory testing for recalling word lists (in serial order and any order) and face-name pairs. Memory control beliefs were assessed at baseline and follow-up using the Memory Controllability Inventory, which consists of four subscales; Present Ability; Potential Improvement; Effort Utility; and Inevitable Decrement. Results: Sixty-three participants (mean age [SD] 68.3 [6.7] years) were included in the analysis. ANCOVA revealed significant group differences in the Present Ability subscale, F2,58 = 4.93, p =.01. Participants in the Memory Training group significantly improved on the Present Ability subscale compared to the Health Education group (mean difference =.96, SE =.31, p =.003, effect size = 0.93). From regression analyses, baseline Memory Controllability Inventory subscales did not significantly predict memory performance after memory training. Conclusions: Baseline memory control beliefs did not predict memory performance following the intervention, but participating in memory training enhanced memory control beliefs about current memory function. These results suggest that participating in memory training can enhance confidence in one's memory ability.

A Randomized Double-Blind Placebo-Controlled Trial of Combined Escitalopram and Memantine for Older Adults With Major Depression and Subjective Memory Complaints.

OBJECTIVE: Geriatric depression is difficult to treat and frequently accompanied by cognitive complaints that increase risk for dementia. New treatment strategies targeting both depression and cognition are urgently needed. METHODS: We conducted a 6-month double-blind placebo-controlled trial to assess the efficacy and tolerability of escitalopram + memantine (ESC/MEM) compared to escitalopram + placebo (ESC/PBO) for improving mood and cognitive functioning in depressed older adults with subjective memory complaints (NCT01902004). Primary outcome was change in depression as assessed by the HAM-D post-treatment (at 6 months). Remission was defined as HAM-D ≤6; naturalistic follow-up continued until 12 months. RESULTS: Of the 95 randomized participants, 62 completed the 6-month assessment. Dropout and tolerability did not differ between groups. Mean daily escitalopram dose was 11.1 mg (SD = 3.7; range: 5-20 mg). Mean daily memantine dose was 19.3 mg (SD = 2.6; range 10-20 mg). Remission rate within ESC/MEM was 45.8% and 47.9%, compared to 38.3% and 31.9% in ESC/PBO, at 3 and 6 months, respectively (χ2(1) = 2.0, p = 0.15). Both groups improved significantly on the HAM-D at 3, 6, and 12 months, with no observed between-group differences. ESC/MEM demonstrated greater improvement in delayed recall (F(2,82) = 4.3, p = 0.02) and executive functioning (F(2,82) = 5.1, p = 0.01) at 12 months compared to ESC/PBO. CONCLUSIONS: The combination of memantine with escitalopram was well tolerated and as effective as escitalopram and placebo in improving depression using HAM-D. Combination memantine and escitalopram was significantly more effective than escitalopram and placebo in improving cognitive outcomes at 12 months. Future reports will address the role of biomarkers of aging in treatment response.

In Vivo Brain Plaque and Tangle Burden Mediates the Association Between Diastolic Blood Pressure and Cognitive Functioning in Nondemented Adults.

OBJECTIVE: Growing evidence supports an association between increased blood pressure and: (a) poor cognitive performance in older adults, and (b) various biomarkers of increased Alzheimer's disease (AD) neuropathology. The objective of this study was to determine whether systolic blood pressure (SBP) and diastolic blood pressure (DBP) were significantly associated with cognitive functioning in non-demented adults, and to examine in vivo AD pathology as a possible mediator of this association. METHODS: Positron emission tomography (PET) scans with 2-(1-{6-[(2-[F-18]fluoroethyl)(methyl)amino]-2-naphthyl}ethylidene)malononitrile (FDDNP) provide in vivo measurements of plaque and tangle burden. A total of 101 non-demented older subjects with blood pressure data and FDDNP-PET scans were drawn from a larger study of predictors of cognitive decline. A neuropsychological test battery was used to compute "global cognitive scores" (averaged across five key domains), which served as an index of general cognitive functioning. RESULTS: Higher DBP (but not SBP) was significantly associated with lower cognitive scores, controlling for age, sex, antihypertensive medication use, and ApoE genotype (η2 = 0.06). However, this relationship was no longer significant after introducing FDDNP-PET binding as an additional covariate in the statistical models. In vivo plaque and tangle burden accounted for over 30% of the observed association between higher DBP and poorer cognitive performance. CONCLUSIONS: By suggesting a mediation of the relationship between DBP and cognitive functioning by FDDNP-PET binding, this study advances our understanding of some potential predictors of cognitive decline in non-demented adults, and underscores the importance of devising early multimodal interventions to more effectively combat degenerative brain disorders.

Modifiable Risk Factors and Brain Positron Emission Tomography Measures of Amyloid and Tau in Nondemented Adults with Memory Complaints.

OBJECTIVE: Exercise and diet impact body composition, but their age-related brain effects are unclear at the molecular imaging level. To address these issues, the authors determined whether body mass index (BMI), physical activity, and diet relate to brain positron emission tomography (PET) of amyloid plaques and tau tangles using 2-(1-(6-[(2-[F-18]fluoroethyl)(methyl)amino]-2-naphthyl)ethylidene)malononitrile (FDDNP). METHODS: Volunteers (N = 44; mean age: 62.6 ± 10.7 years) with subjective memory impairment (N = 24) or mild cognitive impairment (MCI; N = 20) were recruited by soliciting for memory complaints. Levels of physical activity and extent of following a Mediterranean-type diet were self-reported. FDDNP-PET scans assessed plaque/tangle binding in Alzheimer disease-associated regions (frontal, parietal, medial and lateral temporal, posterior cingulate). Mixed models controlling for known covariates examined BMI, physical activity, and diet in relation to FDDNP-PET. RESULTS: MCI subjects with above normal BMI (>25) had higher FDDNP-PET binding compared with those with normal BMI (1.11(0.03) versus 1.08(0.03), ES = 1.04, t(35) = 3.3, p = 0.002). Greater physical activity was associated with lower FDDNP-PET binding in MCI subjects (1.07(0.03) versus 1.11(0.03), ES = 1.13, t(35) = -3.1, p = 0.004) but not in subjects with subjective memory impairment (1.07(0.03) versus 1.07(0.03), ES = 0.02, t(35) = -0.1, p = 0.9). Healthier diet related to lower FDDNP-PET binding, regardless of cognitive status (1.07(0.03) versus 1.09(0.02), ES = 0.72, t(35) = -2.1, p = 0.04). CONCLUSION: These preliminary findings are consistent with a relationship between risk modifiersand brain plaque/tangle deposition in nondemented individuals and supports maintenance of normal body weight, regular physical activity, and healthy diet to protect the brain during aging. (clinicaltrials.gov; NCT00355498).

The patterns of cognitive and functional impairment in amnestic and non-amnestic mild cognitive impairment in geriatric depression.

OBJECTIVES: Depressed older adults are at risk for the development of mild cognitive impairment (MCI), but few studies have characterized MCI subtypes in geriatric depression. The objective of this study was to identify the clinical patterns of MCI in late-life depression. DESIGN: Baseline demographic, clinical, and neuropsychological test data collected as part of a randomized antidepressant trial for geriatric depression. SETTING: UCLA-based outpatient clinic. PARTICIPANTS: One hundred thirty-eight older adults with major depression. MEASUREMENTS: A neuropsychological test battery and comprehensive evaluations of depression, apathy, quality of life, medical burden, and vascular risk factors. RESULTS: Seventy-one participants (51%) had MCI and 67 (49%) were cognitively normal. Of subjects with MCI, 14 (20%) had amnestic MCI and 57 (80%) had non-amnestic MCI. Overall, patients with MCI had greater depression severity, poorer quality of life, and worse performance on the Mini-Mental State Exam than patients without MCI. Patients with non-amnestic MCI had significantly greater depression severity than patients without MCI. Across all subjects, depression severity correlated with impaired performance in language and visuospatial functioning. CONCLUSION: Our findings suggest that MCI is associated with greater severity of depression, poorer quality of life, and worse global cognitive function. Overall, subtypes of MCI in geriatric depression differ in the patterns of functional impairment, which may require different therapeutic approaches.

Psychological well-being and regional brain amyloid and tau in mild cognitive impairment.

OBJECTIVES: To determine whether psychological well-being in people with mild cognitive impairment (MCI), a risk state for Alzheimer disease (AD), is associated with in vivo measures of brain pathology. METHODS: Cross-sectional clinical assessments and positron emission tomography (PET) scans after intravenous injections of 2-(1-{6-[(2-[F18]fluoroethyl)(methyl)amino]-2-naphthyl}ethylidene)malononitrile (FDDNP), a molecule that binds to plaques and tangles, were performed on middle-aged and older adults at a university research institute. Volunteers were aged 40-85 years with MCI (N = 35) or normal cognition (N = 29) without depression or anxiety. Statistical analyses included general linear models, using regional FDDNP-PET binding values as dependent variables and the Vigor-Activity subscale of the Profile of Mood States (POMS) as the independent variable, covarying for age. The POMS is a self-rated inventory of 65 adjectives that describe positive and negative feelings. RESULTS: Scores on the POMS Vigor-Activity subscale were inversely associated with degree of FDDNP binding in the posterior cingulate cortex (r = -0.35, p = 0.04) in the MCI group but not in the control group. CONCLUSION: Psychological well-being, as indicated by self-reports of greater vigor and activity, is associated with lower FDDNP-PET binding in the posterior cingulate cortex, a region involved in emotional regulation, in individuals with MCI but not in those with normal cognition. These findings are consistent with previous work indicating that deposition of brain amyloid plaques and tau tangles may result in noncognitive and cognitive symptoms in persons at risk for AD.

Brain network local interconnectivity loss in aging APOE-4 allele carriers.

Old age and possession of the APOE-4 allele are the two main risk factors for developing later onset Alzheimer's Disease (AD). Carriers of the APOE-4 allele have known differences in intrinsic functional brain network activity across the life span. These individuals also demonstrate specific regional differences in gray and white matter gross structure. However, the relationship of these variations to whole brain structural network connectivity remains unclear. We performed diffusion tensor imaging (DTI), T1 structural imaging, and cognitive testing on aging APOE-4 noncarriers (n = 30; mean age = 63.8±8.3) and APOE-4 carriers (n = 25; mean age = 60.8 ±9.7). Fiber tractography was used to derive whole brain structural graphs, and graph theory was applied to assess structural network properties. Network communication efficiency was determined for each network by quantifying local interconnectivity, global integration, and the balance between these, the small worldness. Relative to noncarriers, APOE-4 carriers demonstrated an accelerated age-related loss of mean local interconnectivity (r = -0.64, P ≤ 0.01) and regional local interconnectivity decreases in the precuneus (r = -0.64), medial orbitofrontal cortex (r = -0.5), and lateral parietal cortex (r = -0.54). APOE-4 carriers also showed significant age-related loss in mean cortical thickness (r = -0.52, P < 0.05). Cognitively, APOE-4 carriers had significant negative correlations of age and performance on two episodic memory tasks (P < 0.05). This genotype-specific pattern of structural connectivity change with age thus appears related to changes in gross cortical structure and cognition, potentially affecting the rate and/or spatial distribution of AD-related pathology.

PET scanning of brain tau in retired national football league players: preliminary findings.

OBJECTIVE: Mild traumatic brain injury due to contact sports may cause chronic behavioral, mood, and cognitive disturbances associated with pathological deposition of tau protein found at brain autopsy. To explore whether brain tau deposits can be detected in living retired players, we used positron emission tomography (PET) scans after intravenous injections of 2-(1-{6-[(2-[F-18]fluoroethyl)(methyl)amino]-2-naphthyl}ethylidene)malononitrile (FDDNP). METHODS: Five retired National Football League players (age range: 45 to 73 years) with histories of mood and cognitive symptoms received neuropsychiatric evaluations and FDDNP-PET. PET signals in subcortical (caudate, putamen, thalamus, subthalamus, midbrain, cerebellar white matter) and cortical (amygdala, frontal, parietal, posterior cingulate, medial and lateral temporal) regions were compared with those of five male controls of comparable age, education, and body mass index. RESULTS: FDDNP signals were higher in players compared with controls in all subcortical regions and the amygdala, areas that produce tau deposits following trauma. CONCLUSIONS: The small sample size and lack of autopsy confirmation warrant larger, more definitive studies, but if future research confirms these initial findings, FDDNP-PET may offer a means for premorbid identification of neurodegeneration in contact-sports athletes.

Healthy behavior and memory self-reports in young, middle-aged, and older adults.

BACKGROUND: Previous research has shown that healthy behaviors, such as regular physical exercise, a nutritious diet, and not smoking, are associated with a lower risk for Alzheimer's disease and dementia. However, less is known about the potential link between healthy behaviors and mild memory symptoms that may precede dementia in different age groups. METHODS: A daily telephone survey (Gallup-Healthways Well-Being Index) of US residents yielded a random sample of 18,552 respondents ranging in age from 18 to 99 years, including 4,423 younger (age 18-39 years), 6,356 middle-aged (40-59 years), and 7,773 older (60-99 years) adults. The questionnaire included demographic information and the Healthy Behavior Index (questions on smoking, eating habits, and frequency of exercise). General linear models and logistic regressions were used in the analysis. RESULTS: Older adults were more likely to report healthy behaviors than were middle-aged and younger adults. Reports of memory problems increased with age (14% of younger, 22% of middle-aged, and 26% of older adults) and were inversely related to the Healthy Behavior Index. Reports of healthy eating were associated with better memory self-reports regardless of age, while not smoking was associated with better memory reports in the younger and middle-aged and reported regular exercise with better memory in the middle-aged and older groups. CONCLUSIONS: These findings indicate a relationship between reports of healthy behaviors and better self-perceived memory abilities throughout adult life, suggesting that lifestyle behavior habits may protect brain health and possibly delay the onset of memory symptoms as people age.

CanCOG®: Cultural Adaptation of the Evidence-Based UCLA Cognitive Rehabilitation Intervention Program for Cancer Survivors in Portugal.

Cognitive difficulties are highly prevalent and negatively impact cancer survivors' quality of life. The UCLA Cognitive Rehabilitation Intervention Program (in short, UCLA program) is an evidence-based intervention developed and tested in the US to address the cognitive complaints of cancer survivors. Since there are no cognitive rehabilitation programs available for Portuguese cancer-related settings, this study aimed to culturally adapt the UCLA program to Portugal. Nine steps were implemented for this cultural adaptation: needs assessment, initial contacts, translation, cultural adaptation, independent review by a panel of experts (n = 6), focus group discussions with cancer survivors (n = 11), systematization of inputs and improvement of the final materials, fidelity check, and preliminary acceptability assessment. The findings suggested that changes to the original materials were needed. A Portuguese name, "CanCOG®-Reabilitação Cognitiva no Cancro" (in English "CanCOG®-Cognitive Rehabilitation in Cancer"), and a logo were created to make it more memorable and appealing for the Portuguese population. The language was adjusted to ensure content accessibility and semantic and conceptual equivalence. Finally, references to several cultural aspects, such as habits, customs, and traditions, were adapted to fit the new cultural context. The UCLA program may be a promising tool to help alleviate the cognitive difficulties reported by cancer survivors in different cultural contexts. Future research is needed to confirm the feasibility, acceptability, and preliminary efficacy of its Portuguese version, "CanCOG®-Reabilitação Cognitiva no Cancro".

Influence of Alzheimer disease family history and genetic risk on cognitive performance in healthy middle-aged and older people.

OBJECTIVES: Identification of risk factors for Alzheimer disease (AD) is critical for establishing effective diagnostic and therapeutic strategies. Carrying the ε4 allele of the apolipoprotein E gene (APOE4) and having a family history of the disease are two such factors, with family history risk reflecting additional yet unknown or rarely studied genetic and perhaps nongenetic risks. Our aim was to determine the influence of APOE genotype and family history status on cognitive performance in healthy individuals. DESIGN: Longitudinal study. SETTING: Semel Institute for Neuroscience and Human Behavior, University of California, Los Angeles. PARTICIPANTS: Seventy-two cognitively healthy middle-aged and older people (mean age ± SD: 62 ± 9 years). MEASUREMENTS: Neuropsychological examinations at baseline and after 2 years. RESULTS: Subjects with a family history of AD had lower baseline scores in processing speed, executive functioning, memory encoding, and delayed memory when compared with those without a family history. The family history risk factor did not influence degree of cognitive decline over time. By contrast, baseline cognitive performance did not vary according to APOE4 carrier status. Non-APOE4 carriers showed improved cognitive performance in the memory domains at follow-up, while performance of APOE4 carriers did not change. CONCLUSIONS: Our data highlight the unique contributions of each risk factor to cognitive performance in healthy people. Both factors should be modeled in neuropsychological assessments of people at risk for AD.

The memory fitness program: cognitive effects of a healthy aging intervention.

CONTEXT: Age-related memory decline affects a large proportion of older adults. Cognitive training, physical exercise, and other lifestyle habits may help to minimize self-perception of memory loss and a decline in objective memory performance. OBJECTIVE: The purpose of this study was to determine whether a 6-week educational program on memory training, physical activity, stress reduction, and healthy diet led to improved memory performance in older adults. DESIGN: A convenience sample of 115 participants (mean age: 80.9 [SD: 6.0 years]) was recruited from two continuing care retirement communities. The intervention consisted of 60-minute classes held twice weekly with 15-20 participants per class. Testing of both objective and subjective cognitive performance occurred at baseline, preintervention, and postintervention. Objective cognitive measures evaluated changes in five domains: immediate verbal memory, delayed verbal memory, retention of verbal information, memory recognition, and verbal fluency. A standardized metamemory instrument assessed four domains of memory self-awareness: frequency and severity of forgetting, retrospective functioning, and mnemonics use. RESULTS: The intervention program resulted in significant improvements on objective measures of memory, including recognition of word pairs (t([114]) = 3.62, p <0.001) and retention of verbal information from list learning (t([114]) = 2.98, p <0.01). No improvement was found for verbal fluency. Regarding subjective memory measures, the retrospective functioning score increased significantly following the intervention (t([114]) = 4.54, p <0.0001), indicating perception of a better memory. CONCLUSIONS: These findings indicate that a 6-week healthy lifestyle program can improve both encoding and recalling of new verbal information, as well as self-perception of memory ability in older adults residing in continuing care retirement communities.

Self-reported memory impairment and brain PET of amyloid and tau in middle-aged and older adults without dementia.

BACKGROUND: Whether perceived changes in memory parallel changes in brain pathology is uncertain. Positron emission tomography (PET) scans using 2-(1-{6-[(2-[F-18]fluoroethyl)(methyl)amino]-2-naphthyl}ethylidene)malononitrile (FDDNP) can measure levels of amyloid plaques and tau neurofibrillary tangles in vivo. Here we investigate whether degree of self-reported memory impairment is associated with FDDNP-PET binding levels in persons without dementia. METHODS: Fifty-seven middle-aged and older adults without dementia (mean age ±standard deviation = 66.3 ± 10.6 years), including 25 with normal aging and 32 with mild cognitive impairment (MCI), were assessed. The outcome measures were the four factor scores of the Memory Functioning Questionnaire (MFQ) (frequency of forgetting, seriousness of forgetting, retrospective functioning, and mnemonics use) and FDDNP-PET binding levels in medial temporal, lateral temporal, posterior cingulate, parietal, frontal, and global (overall average) regions of interest. RESULTS: After controlling for age, higher reported frequency of forgetting was associated with greater medial temporal (r = -0.29, p = 0.05), parietal (r = -0.30, p = 0.03), frontal (r = -0.35, p = 0.01), and global FDDNP-PET binding levels (r = -0.33, p = 0.02). The remaining MFQ factor scores were not significantly associated with FDDNP-PET binding levels, and no significant differences were found between normal aging and MCI subjects. Item analysis of the frequency of forgetting factor revealed five questions that yielded similar results as the full 32-question scale (r = -0.52, p = 0.0002). CONCLUSIONS: These findings suggest that some forms of memory self-awareness, in particular the reported frequency of forgetting, may reflect the extent of cerebral amyloid and tau brain pathology.

Complementary use of tai chi chih augments escitalopram treatment of geriatric depression: a randomized controlled trial.

BACKGROUND: Nearly two-thirds of elderly patients treated for depression fail to achieve symptomatic remission and functional recovery with first-line pharmacotherapy. In this study, we ask whether a mind-body exercise, Tai Chi Chih (TCC), added to escitalopram will augment the treatment of geriatric depression designed to achieve symptomatic remission and improvements in health functioning and cognitive performance. METHODS: : One hundred twelve older adults with major depression age 60 years and older were recruited and treated with escitalopram for approximately 4 weeks. Seventy-three partial responders to escitalopram continued to receive escitalopram daily and were randomly assigned to 10 weeks of adjunct use of either 1) TCC for 2 hours per week or 2) health education (HE) for 2 hours per week. All participants underwent evaluations of depression, anxiety, resilience, health-related quality of life, cognition, and inflammation at baseline and during 14-week follow-up. RESULTS: Subjects in the escitalopram and TCC condition were more likely to show greater reduction of depressive symptoms and to achieve a depression remission as compared with those receiving escitalopram and HE. Subjects in the escitalopram and TCC condition also showed significantly greater improvements in 36-Item Short Form Health Survey physical functioning and cognitive tests and a decline in the inflammatory marker, C-reactive protein, compared with the control group. CONCLUSION: : Complementary use of a mind-body exercise, such as TCC, may provide additional improvements of clinical outcomes in the pharmacologic treatment of geriatric depression.

Increasing depressive symptoms in children of Alzheimer parents.

Children of persons with Alzheimer disease (AD) are at increased risk of developing AD themselves, but specific factors that predict AD in this population have yet to be elucidated. Various studies indicate depressive symptoms may predate clinical AD and represent a risk factor and/or prodrome of incipient dementia, but their relevance for AD offspring remains uncertain. As part of a longitudinal family study of AD, we assessed depressive symptomatology in 30 middle aged AD offspring (mean age at baseline: 41.2). Their mean total scores on the Hamilton Depression Rating scale increased from 1.8 to 5.3 (P < .001) across a 20-year interval. Neurocognitive performance remained stable in a subset of this cohort (N = 25) over the same interval. Findings from this small convenience sample suggest emerging depressive symptoms may be among the earliest signs of subsequent dementia in this high-risk population but require confirmation through further longitudinal follow-up and replication in larger populations.

Reduced hippocampal CA2, CA3, and dentate gyrus activity in asymptomatic people at genetic risk for Alzheimer's disease.

Previous functional magnetic resonance imaging (MRI) studies in healthy subjects with the apolipoprotein Eepsilon4 (APOE-4) genetic risk for Alzheimer's disease have shown increased activation during memory task performance in broadly distributed cortical regions. These findings have been hypothesized to reflect compensatory recruitment of intact brain regions that presumably result from subtle neural dysfunction reflecting incipient disease. In this study, we used high-resolution functional MRI in APOE-4 carriers and non-carriers to measure activity in hippocampal subregions (CA fields 1, 2, 3; dentate gyrus [DG], and subiculum) and adjacent medial temporal lobe (parahippocampal and entorhinal) subregions. We found reduced left CA2, CA3, and dentate gyrus (CA23DG) activity in cognitively intact APOE-4 carriers. These results suggest that reduced neural activity in hippocampal subregions may underlie the compensatory increase in extrahippocampal activity in people with a genetic risk for Alzheimer's disease prior to the onset of cognitive deficits.

Longitudinal changes in medial temporal cortical thickness in normal subjects with the APOE-4 polymorphism.

People with the apolipoprotein-Eepsilon4 (APOE-4) genetic risk for Alzheimer's disease show morphologic differences in medial temporal lobe regions when compared to non-carriers of the allele. Using a high-resolution MRI and cortical unfolding approach, our aim was to determine the rate of cortical thinning among medial temporal lobe subregions over the course of 2 years. We hypothesized that APOE-4 genetic risk would contribute to longitudinal cortical thickness change in the subiculum and entorhinal cortex, regions preferentially susceptible to Alzheimer's disease related pathology. Thirty-two cognitively intact subjects, mean age 61 years, 16 APOE-4 carriers, 16 non-carriers, underwent baseline and follow-up MRI scans. Over this relatively brief interval, we found significantly greater cortical thinning in the subiculum and entorhinal cortex of APOE-4 carriers when compared to non-carriers of the allele. Average cortical thinning across all medial temporal lobe subregions combined was also significantly greater for APOE-4 carriers. This finding is consistent with the hypothesis that carrying the APOE-4 allele renders subjects at a higher risk for developing Alzheimer's disease.

Memantine can protect against inflammation-based cognitive decline in geriatric depression.

INTRODUCTION: Geriatric depression is frequently accompanied by cognitive complaints and inflammation that increase risk for treatment-resistant depression and dementia. Memantine, a neuroprotective drug, can improve depression, inflammation, and help prevent cognitive decline. In our six-month clinical trial, escitalopram/memantine (ESC/MEM) improved mood and cognition compared to escitalopram/placebo treatment (ESC/PBO; NCT01902004). In this report, we examined the impact of baseline inflammation on mood and cognitive outcomes. MATERIALS AND METHODS: We measured a panel of inflammatory cytokine markers using Human 38-plex magnetic cytokine/chemokine kits (EMD Millipore, HCYTMAG-60K-PX38) in 90 older adults 60 years and older with major depression enrolled in a 6-month double-blind placebo-controlled trial of escitalopram â€‹+ â€‹memantine (ESC/MEM) in depressed older adults with subjective memory complaints. Four cytokine factors were derived and linear models were estimated to examine the predictive ability of cytokine levels on treatment induced change in depression and cognition. RESULTS: Of the 90 randomized participants, 62 completed the 6-month follow up assessment. Both groups improved significantly on depression severity (HAM-D score), but not on cognitive outcomes at six months. Cytokine factor scores were not significantly different between ESC/MEM (n â€‹= â€‹45) and ESC/PBO (n â€‹= â€‹45) at baseline. Pro-inflammatory biomarkers at baseline predicted a decline in executive functioning in the ESC/PBO group but not in the ESC/MEM group, interaction F(1,52) â€‹= â€‹4.63, p â€‹= â€‹.04. DISCUSSION: In this exploratory analysis, the addition of memantine to escitalopram provided a protective effect on executive functioning in older depressed adults. Future studies are needed to replicate the association of cytokine markers to antidepressant and neuroprotective treatment-related change in cognition in geriatric depression.

Randomized placebo-controlled study of the memory effects of pomegranate juice in middle-aged and older adults.

BACKGROUND: Antioxidant nutrients such as the polyphenols in pomegranate juice may prevent neuronal damage from the free radicals produced during normal metabolism. Previous research in animals and a short-term clinical trial in middle-aged and older adults support the potential memory benefits of pomegranate juice; however, the long-term effects of pomegranate juice consumption on cognition have not been studied. OBJECTIVE: In this study, we investigated the long-term effect of pomegranate juice on memory in nondemented middle-aged and older adults. METHODS: We performed a 12-month, randomized, double-blind, placebo-controlled trial of pomegranate juice in middle-aged and older adults. Two hundred and sixty-one subjects (aged 50-75 y) were randomly assigned to consume pomegranate juice [8 oz (236.5 mL) per day] or a placebo drink (8 oz, matched constituents of pomegranate juice except for pomegranate polyphenols). Memory measures [Brief Visuospatial Memory Test-Revised (BVMT-R) and Buschke Selective Reminding Test (SRT)] were assessed at 6 and 12 mo and analyzed using a mixed-effects general linear model. RESULTS: Twenty-eight subjects in the pomegranate juice group and 33 subjects in the placebo group dropped out before completing the study. Baseline variables in the 98 pomegranate juice and 102 placebo group subjects who completed the study did not differ significantly. Group by time interaction was statistically significant for BVMT-R Learning (F[2, 257]= 5.90, P = 0.003; between-group effect size [ES] = 0.45): the change within the pomegranate group was not significant (ES = 0.15), whereas the placebo group showed a significant decline (ES = -0.35). Changes in the other BVMT-R scores as well as the SRT measures were not significantly different between groups. CONCLUSIONS: Daily consumption of pomegranate juice may stabilize the ability to learn visual information over a 12-mo period. This trial was registered at clinicaltrials.gov as NCT02093130.