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Background Depression has been associated with higher conversion rates from mild cognitive impairment (MCI) to Alzheimer’s disease (AD) and may be a potential clinical marker of prodromal AD that can be used to identify individuals with MCI who are most likely to progress to AD. Using tensor-based morphometry (TBM), we examined the longitudinal neuroanatomical changes associated with depressive symptoms in MCI. Methods 243 MCI subjects from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) who had brain MRI scans at baseline and 2-year follow-up were classified into depressed (DEP, n=44), non-depressed with other neuropsychiatric symptoms (OTHER, n=93), and no-symptom (NOSYMP, n=106) groups based on the Neuropsychiatric Inventory Questionnaire (NPI-Q). TBM was used to create individual 3D-maps of 2-year brain changes that were compared between groups. Results DEP subjects had more frontal (p=0.024), parietal (p=0.030), and temporal (p=0.038) white matter atrophy than NOSYMP subjects. A subset of DEP subjects whose depressive symptoms persisted over 2-years also had higher conversion to AD and more decline on measures of global cognition, language abilities, and executive functioning compared to stable NOSYMP subjects. OTHER and NOSYMP groups exhibited no differences in rates of atrophy. Conclusions Depressive symptoms in MCI subjects were associated with greater atrophy in AD-affected regions, increased cognitive decline, and higher rates of conversion to AD. Depression in individuals with MCI may be associated with underlying neuropathological changes including prodromal AD. Thus, assessment of depressive symptoms may be a potentially useful clinical marker in identifying MCI patients who are most likely to progress to AD.

Background Walnut consumption counteracts oxidative stress and inflammation, 2 drivers of cognitive decline. Clinical data concerning effects on cognition are lacking. Objectives The Walnuts And Healthy Aging study is a 2-center (Barcelona, Spain; Loma Linda, CA) randomized controlled trial examining the cognitive effects of a 2-y walnut intervention in cognitively healthy elders. Methods We randomly allocated 708 free-living elders (63–79 y, 68% women) to a diet enriched with walnuts at ∼15% energy (30–60 g/d) or a control diet (abstention from walnuts). We administered a comprehensive neurocognitive test battery at baseline and 2 y. Change in the global cognition composite was the primary outcome. We performed repeated structural and functional brain MRI in 108 Barcelona participants. Results A total of 636 participants completed the intervention. Besides differences in nutrient intake, participants from Barcelona smoked more, were less educated, and had lower baseline neuropsychological test scores than those from Loma Linda. Walnuts were well tolerated and compliance was good. Modified intention-to-treat analyses (n = 657) uncovered no between-group differences in the global cognitive composite, with mean changes of −0.072 (95% CI: −0.100, −0.043) in the walnut diet group and −0.086 (95% CI: −0.115, −0.057) in the control diet group (P = 0.491). Post hoc analyses revealed significant differences in the Barcelona cohort, with unadjusted changes of −0.037 (95% CI: −0.077, 0.002) in the walnut group and −0.097 (95% CI: −0.137, −0.057) in controls (P = 0.040). Results of brain fMRI in a subset of Barcelona participants indicated greater functional network recruitment in a working memory task in controls. Conclusions Walnut supplementation for 2 y had no effect on cognition in healthy elders. However, brain fMRI and post hoc analyses by site suggest that walnuts might delay cognitive decline in subgroups at higher risk. These encouraging but inconclusive results warrant further investigation, particularly targeting disadvantaged populations, in whom greatest benefit could be expected. This trial was registered at clinicaltrials.gov as NCT01634841.

The aging population is expanding, as is the prevalence of age-related cognitive decline (ARCD). Of the several risk factors that predict the onset and progression of ARCD, 2 important modifiable risk factors are diet and physical activity. Dietary patterns that emphasize plant foods can exert neuroprotective effects. In this comprehensive review, we examine studies in humans of plant-based dietary patterns and polyphenol-rich plant foods and their role in either preventing ARCD and/or improving cognitive function. As yet, there is no direct evidence to support the benefits of a vegetarian diet in preventing cognitive decline. However, there is emerging evidence for brain-health–promoting effects of several plant foods rich in polyphenols, anti-inflammatory dietary patterns, and plant-based dietary patterns such as the Mediterranean diet that include a variety of fruits, vegetables, legumes, nuts, and whole grains. The bioactive compounds present in these dietary patterns include antioxidant vitamins, polyphenols, other phytochemicals, and unsaturated fatty acids. In animal models these nutrients and non-nutrients have been shown to enhance neurogenesis, synaptic plasticity, and neuronal survival by reducing oxidative stress and neuroinflammation. In this review, we summarize the mounting evidence in favor of plant-centered dietary patterns, inclusive of polyphenol-rich foods for cognitive well-being. Randomized clinical trials support the role of plant foods (citrus fruits, grapes, berries, cocoa, nuts, green tea, and coffee) in improving specific domains of cognition, most notably frontal executive function. We also identify knowledge gaps and recommend future studies to identify whether plant-exclusive diets have an added cognitive advantage compared with plant-centered diets with fish and/or small amounts of animal foods.

The C-terminus of the most abundant and best-studied gap-junction protein, connexin43, contains multiple phosphorylation sites and protein-binding domains that are involved in regulation of connexin trafficking and channel gating. It is well-documented that SDS/PAGE of NRK (normal rat kidney) cell lysates reveals at least three connexin43-specific bands (P0, P1 and P2). P1 and P2 are phosphorylated on multiple, unidentified serine residues and are found primarily in gap-junction plaques. In the present study we prepared monoclonal antibodies against a peptide representing the last 23 residues at the C-terminus of connexin43. Immunofluorescence studies showed that one antibody (designated CT1) bound primarily to connexin43 present in the Golgi apparatus, whereas the other antibody (designated IF1) labelled predominately connexin43 present in gap junctions. CT1 immunoprecipitates predominantly the P0 form whereas IF1 recognized all three bands. Peptide mapping, mutational analysis and protein-protein interaction experiments revealed that unphosphorylated Ser364 and/or Ser365 are critical for CT1 binding. The IF1 paratope binds to residues Pro375-Asp379 and requires Pro375 and Pro377. These proline residues are also necessary for ZO-1 interaction. These studies indicate that the conformation of Ser364/Ser365 is important for intracellular localization, whereas the tertiary structure of Pro375-Asp379 is essential in targeting and regulation of gap junctional connexin43.