**4. Association between Nuts and Cognitive Disorders**

Inflammation-associated chronic pathologies, such as dementia, Parkinson's disease (PD), or Alzheimer's disease (AD), lead to one of the most unfavorable health problems in the elderly: age-related cognitive deterioration, a condition which may be prevented or delayed by modifiable lifestyle factors, including antioxidant diets [117].

Quite a few studies have examined the association between diets supplemented with nuts and cognitive performance [118–124] (Table 6).

In an elderly population, consumption of walnuts was related to better cognitive performance, mainly working memory, although the causality could not be inferred [120]. These results were consistent with another cross-sectional study that indicated a positive association between nut consumption and cognitive function in mature Chinese adults. Patients with mild cognition impairment symptoms had less tree nuts and peanuts in their diet compared to healthy subjects (*p* = 0.031) [125]. Similarly, positive relations between cognitive functions and nut intake were shown in the US population. Significant improvements in almost all cognitive test scores were noted among older adults who added walnuts in their diet [126].

The scores from two neuropsychological tests, the Mini-Mental State Examination (an indicator of cognitive impairment) and the Clock Drawing Test (a neuropsychological test which evaluates cognitive decline and dementia), were higher for subjects allocated to the nut-enhanced MD compared to the low-fat, nut-free diet group [121]. Comparable results were obtained by Valls-Pedret et al. [123]; in an older population, MD supplemented with tree nuts (walnuts, almonds, hazelnuts) was associated with improved cognitive functions. Also, a high consumption of tree nuts and peanuts was linked to better cognitive function at baseline and might reduce cognitive decline in mature adults [119]. Equally, O'Brien et al. [122] suggested that long-term tree nut and peanut intake was related to overall level of cognition but had no effect on cognitive decline.

A recent RCT demonstrated that peanut consumption could improve vascular and cognitive functions in overweight middle-aged subjects. Small artery elasticity, cerebrovascular reactivity, as well as measures of verbal fluency, processing speed, and short-term memory were all greater after higher intake of roasted, unsalted peanuts with skin [124]. Also, the addition of walnuts (15% of energy) to an ad libitum diet confirmed that regular nut consumption can delay the onset of age-related neurodegenerative disorders. Compared with the control, individuals in the walnut group reported significantly lower intake of animal protein, total carbohydrates, saturated fatty acids, and sodium, but significantly higher ingestion of vegetable protein, antioxidant *n*-3 and *n*-6 PUFAs [127].

Brain-derived neurotrophic factor (BDNF), a protein belonging to the neurotrophic family, controls axonal elongation, neurotransmitter release, growth, differentiation, and survival of presynaptic structure. While low plasma levels of BDNF could lead to the atrophy of specific brain areas in mammals such as the hippocampus and frontal cortex. Higher concentrations of BDNF provided by enhanced-nut MD were likely to prevent depression, memory loss, and cognitive decline [118]. It seems that *n*-3 PUFA, with its powerful antioxidant potential, is responsible for the increased levels of the BDNF signaling factor [128]. Blondeau et al. [129] noticed that alpha-linolenic acid (ALA), the plant-based *n*-3 PUFA, may increase BDNF, thus walnut intake can have a role in neuroprotection, neuroplasticity, and vasodilation of brain arteries.

Major depressive disorder (MDD) is a chronic disease where healthy dietary practices in combination with current treatments may prevent or delay its evolution. Increased consumption of nuts, seeds, vegetables, fruits, and legumes, with proven antioxidant and anti-inflammatory capacities, is the principal nutritional recommendation, with a key reminder that the beneficial effects are possible to come from wholesome nutritious diets rather than from individual nutrients [130]. Ali-Sisto et al. [131] showed that MDD is characterized by a decreased arginine level, an amino acid found in nuts and a precursor of NO, which is needed to modulate neuronal and vasodilation functions, to prevent oxidation of LDL-C, aggregation of platelets, or vascular inflammation, and inhibit oxidation in the central nervous system (CNS). MDD is associated with increased CV events, and the biological mechanism connecting MDD and CVD is apparently a chronic inflammation induced by a low level or bioavailability of arginine [131].



\* low-fat diet—all types of fat, from both animal and vegetable sources, reduced, but no fat-free foods. A—almonds; BDNF—brain-derived neurotrophic factor; CDT—Clock Drawing Test; CI—confidence interval; F—women; H—hazelnuts; M—men; MD—Mediterranean diet; MMSE—Mini-Mental State Examination; OR—odds ratio; RCT—randomized controlled trial; W—walnuts.

A study on Chinese adults demonstrated that, even after adjusting for potential confounders, the frequency of tree nut and peanut intake (more than 4 times per week) might be associated with a lower incidence of depressive symptoms [132]. Also, Arab et al. [133] reported that U.S. nut consumers, especially walnut eaters, had significantly lower depression scores as compared to no-nut consumers, and the difference was strongest among women.

Optimal dietary choices, such as increasing bioactive antioxidant compound intake through higher nut, fruit, and vegetable consumption, can improve endothelial function, decrease inflammatory biomarkers, protect neuronal and cell-signaling function, increase cognitive performance, and prevent or delay the onset of cognitive dysfunction during aging [134]. In anxiety-based psychopathology, replacing pro-inflammatory saturated fats with anti-inflammatory walnut oil might result in faster, more profound elimination of fear-based learning [135].
