Cognition is defined as the ability to learn, think, solve problems, remember, and communicate. Cats and dogs can age in a manner wherein age-related changes have minimal impact, or they may develop cognitive decline (comparable to mild cognitive impairment in humans) or more severe cognitive dysfunction syndrome (comparable to dementia and Alzheimer disease in humans)1.
Age-associated changes in the brain include regional atrophy of gray and white matter, increases in ventricular volume, irreversible loss of neurons and synapses, reduced neurogenesis, reduced clearance and subsequent accumulation of abnormal proteins (such as b-amyloid), inflammation, oxidative stress, vascular changes (including cerebral amyloid angiopathy), reduction or deterioration of myelin, diminished cholinergic function, and alterations in gene expression. Energy metabolism in the brain is also altered with age. Compromised mitochondrial function reduces energy availability and contributes to increased production of oxygen free radicals and oxidative stress. Oxidative stress is also associated with neurodegenerative diseases and cognitive decline1.
Aged dogs are a higher mammalian model system that naturally accumulates human-type pathology and cognitive decline, so research has been conducted on the effect of various nutrient combinations on reversing/preventing this condition. In canines, although Aβ is primarily deposited as diffuse plaques in the canine brain, there is an association between the extent of Aβ and cognitive decline2. In addition to this, a significant correlation was found between behavior changes and several measures of oxidative damage3.
Fish Oil (60% Docosahexaenoic Acid)
Long-chain omega-3 fatty acids (e.g., alpha-linolenic acid (ALA), docosahexaenoic acid (DHA), eicosapentaenoic acid (EPA)), prevalent in oily fish, may decrease beta-amyloid deposition, prevent neuronal loss, improve cognition, and reduce inflammation in animal models 4-6. Increased intake of long-chain omega-3 PUFAs protects against cognitive decline or improves cognitive function in mice7 and humans8,9. In humans, meta-analysis drawing from cohort studies failed to find an association between total omega-3 consumption and AD risk, but did note that for every 0.1 g/day incremental increase in dietary DHA, there was a 37% reduced risk of AD10.
The omega-3 PUFAs, in particular DHA, play critical neuroprotective and anti-inflammatory roles in the brain. Neural tissues are rich in DHA, but aging is accompanied by a reduction in DHA content in the brain, which favours neurodegeneration7-8. The beneficial neurophysiological actions of DHA occur in part through its direct maintenance of neuronal plasma membrane fluidity and functional integrity, and in part through the generation of docosanoids11. Various studies underline the importance of DHA-derived neuroprotectin D1 (NPD1) in the homeostatic regulation of brain cell survival and repair involving neurotrophic, antiapoptotic and anti-inflammatory signalling12.
The role of DHA in brain function has also been the focus of another study13, where dietary fortification with fish oils rich in DHA and possibly other nutrients implicated in neurocognitive development following weaning improved cognitive, memory, psychomotor, immunologic, and retinal functions in growing dogs.
In another series of studies, dietary supplementation with a nutrient blend containing arginine, antioxidants, B vitamins and fish oil was assessed as to its potential of cognitive enhancement in middle-aged and old cats14 and old dogs15. The cats fed the test diet showed significantly better performance on three of four test protocols: a protocol assessing egocentric learning, a protocol assessing discrimination and reversal learning and a protocol focused on acquisition of a spatial memory task. Similarly, the study on dogs revealed that the supplemented group showed significantly better performance than the controls on the landmark 1 (P = 0·0446) discrimination learning tasks, and on two egocentric discrimination reversal learning tasks (P = 0·005 and P = 0·01, respectively). Both these results indicate that long-term supplementation with a brain protective nutrient blend containing arginine, antioxidants, B vitamins and fish oil can have cognition-improving effects and support the use of nutritional strategies in targeting brain ageing associated risk factors as an intervention to delay cognitive ageing.
Choline is a micronutrient and a methyl donor that is required for normal brain growth and development. It plays a pivotal role in maintaining structural and functional integrity of cellular membranes. It also regulates cholinergic signalling in the brain via the synthesis of acetylcholine. Via its metabolites, it participates in pathways that regulate methylation of genes related to memory and cognitive functions at different stages of development. Choline-related functions have been dysregulated in some neurodegenerative diseases suggesting choline plays an important role in influencing mental health across the lifespan16.
The role of the micronutrient choline and other methyl-donors in the functioning of the mature brain has been studied in animal models and in humans. For example, choline has been shown to exert neuroprotective effects by lessening or delaying symptoms of cognitive impairments and memory decline with aging17-19, symptoms often seen in individuals suffering from neurodegenerative disorders such as Alzheimer’s disease.
Administration of a choline-based combination nutraceutical lessened confusion and improved appetite in aged cats20
Lipoic acid and L-carnitine
Mitochondrial dysfunction and production of ROS may be a key contributor to the deleterious effects of aging on the brain. Co-factors that specifically target the mitochondria to improve efficiency and reduce ROS such as acetyl-l-carnitine (ALCAR) and lipoic acid (LA) have been found to lead to behavioral improvements and reduced oxidative damage in the brains of aged rodents21.
L-carnitine and acetyl-L-carnitine are essential in the transportation of long chain fatty acids into the cell, acting as signaling and metabolic enhancers. A-lipoic acid is an endogenous antioxidant, which has been shown to recycle other enzymatic antioxidants. The combination of acetyl-L-carnitine and a-lipoic acid showed a greater effect than either of the components alone22 and results suggested that feeding a combination of mitochondrial metabolites to old animals may prevent mitochondrial decay in neurons and restore cognitive dysfunction.
In aged beagle dogs, Acetyl-L-carnitine and α-lipoic acid supplementation improved learning in two landmark discrimination tests23. It was thus suggested that long-term maintenance on LA and ALC may be effective in attenuating age-associated cognitive decline by slowing the rate of mitochondrial decay and cellular aging.
In a small placebo-controlled clinical trial on 44 dogs aged over 8 years old with a total duration of 56 days, a combination nutritional supplement containing LA, and ALCAR, among others, indicate a clear beneficial effect of nutritional supplementation on some aspects of behavior-associated with canine cognitive dysfunction24.
A longitudinal investigation of the effects of dietary antioxidant intervention on cognitive function of aged beagle dogs comprising (ALCAR) and lipoic acid (LA), cellular antioxidants, fruits and vegetables, led to rapid learning improvements, memory improvements after prolonged treatment and cognitive maintenance25.
In a newer study for the evaluation of the effects of specific components of diet supplementation which contain both antioxidants and a combination of mitochondrial cofactors (lipoic acid [LA] and acetyl-l-carnitine) on a battery of cognitive functions, data suggested that supplementation with mitochondrial cofactors, but not LA or antioxidant alone, selectively improve long-term recall in aged canines26.
MERIVA® -Turmeric Phytosome®* – pure Turmeric extract
Curcuma longa is a Southeast Asian plant, having an orange rhizome with a strongly aromatic smell. The mixture of curcuminoids, obtained as an extract from the turmeric powder of Curcuma longa is constituted by the most abundant curcumin, demethoxycurcumin, bisdemethoxycurcumin and cyclocurcumin. They are provided with important pharmacological activities, such as antioxidant, antiangiogenic, anti-inflammatory, antiviral and anticancer. The lower incidence rates of AD in the populations of South East Asia, the main consumers of turmeric, are associated with regular curcumin consumption, which is efficacious to counteract the neurophysiological damages occurring during the disease27. Single curcuminoids have been found to interact with Aβ-peptide, preventing or disaggregating β-amyloid fibrils, thus acting as anti-Alzheimer agents27.
Curcumin has received increased interest due to its unique molecular structure that targets inflammatory and antioxidant pathways as well as (directly) amyloid aggregation, one of the major hallmarks of Alzheimer’s disease. Overall, animal research has shown very promising results in potentiating cognition, both physiologically and behaviorally. The majority of studies have reported superiority of curcumin compared to the control group28. A number of preclinical studies have reported downregulation of biomarkers of inflammation (e.g. TNF-α, IL-1β) and oxidative stress (e.g. lipid peroxidation, ROS, nitrite and glutathione) believed to be involved in cognitive impairments, confirming the anti-inflammatory and antioxidant properties of curcumin29-31. Increased neurogenesis observed after treatment with curcumin or initiation of autophagy suggest other possible actions of this compound in potentiating cognition32-34.
However, its main drawback is the low bioavailability due to poor solubility, low absorption, rapid metabolism, and rapid excretion35-36. The Phytosome® is the only delivery system in the world entirely made of natural elements and for this reason is thoroughly food grade, as it manages to mimic the absorption of a fatty meal. Curcumin Phytosome® is not only bioavailable and bio-absorbable at an endogenous level, but effective, tolerable over a long period of time and safe37.
Rosemary leaves extract – 10% Total Terpenes (5% Carnosic acid)
Rosemary (Rosmarinus officinalis L.) diterpenes have been shown in recent years to inhibit neuronal cell death induced by a variety of agents both in vitro and in vivo. The therapeutic potential of these compounds for Alzheimer’s disease has been researched, based on the multifunctional nature of the compounds from the general antioxidant-mediated neuronal protection to other specific mechanisms including brain inflammation and amyloid beta (A????) formation, polymerization, and pathologies38.
Only Carnosic acid (CA) and Carnosol, the major diterpenes which account for over 90 % of its antioxidant activity in rosemary leaves, have been extensively investigated for their possible therapeutic effect related to AD39. In the work by Azad et al40, CA (10 mg/kg, i.p. 1 h before surgery, followed by CA at 3 mg/kg, i.p. 3–4 h after surgery with repetitions once a day during 12 days) protected rat hippocampus from amyloid-β-induced lesions in an experimental model of Alzheimer’s disease.
In another study, the results revealed that rosemary extract (40% Carnosic acid) may improve the memory score and oxidative stress activity in middle aged rats in a dose dependent manner, especially in those fed with 100mg/kg/day41. A possible mechanism of action has been elucidated in a different study, where the subchronic (28-fold) administration of Rosemary extract (200 mg/kg, p.o.) was assessed as to its effects on behavioural and cognitive responses of rats linked with acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) activity and their mRNA expression level in the hippocampus and frontal cortex. RE inhibited the AChE activity and showed a stimulatory effect on BuChE in both parts of rat brain. Moreover, RE produced a lower mRNA BuChE expression in the cortex and simultaneously an increase in the hippocampus. The study suggests that RE led to improved long-term memory in rats, which can be partially explained by its inhibition of AChE activity in rat brain42.
The amino acid L-arginine serves several roles, including an antioxidant function. It is metabolized in neurons and other cells to form citrulline, which results in the formation of nitric oxide. The high metabolic activity of the brain during cognitive tasks results in the use of more oxygen; thus, cognitive activity requires an increase in blood flow, which is primarily mediated by nitric oxide43.
In previously mentioned studies of cats14 and dogs15 fed a diet supplemented with L-arginine at amounts above the proposed daily requirement in addition to fatty acids, antioxidants, and other nutrients revealed cognitive benefits for animals fed the supplemented diet, although the extend to which L-arginine alone was beneficial could not be determined.
Administration of L-arginine during one month significantly improved memory acquisition in 3xTg-AD mice and led to upregulation of several critical biological processes, including stress defense, response to oxygen-containing compounds, and metabolism of nitrogen compounds. It was suggested that the cognitive effect of L-arginine administration is not related to the reduction of amyloid plaques formation or facilitation of neuroplasticity (LTP), but associated with cytoprotective and antiapoptotic potentials of arginine44.
Vitamin E has been shown to act as nutritional antioxidant preventing the nervous system from free radical oxidative damage45.
In a study with a rat model of Alzheimer’s disease, treatment with vitamin E (25, 50, and 100 mg/kg/day) for 14 days resulted in a significant decrease in the mean number of congophilic amyloid plaques and the number of neurofibrillary tangles in the hippocampus of male rats treated with scopolamine46.
In another mechanism research study, evidence suggested that vitamin E may act through activation of cholinergic system on memory retention47. Vitamin E prevents lowering of level of Ach in some parts of brain, which are involved in memory retention process. Also, vitamin E may affect sensitivity of cholinoceptors in the brain.
In a small placebo-controlled clinical trial on 44 dogs aged over 8 years old with a total duration of 56 days, a combination nutritional supplement containing vitamin E, among others, indicate a clear beneficial effect of nutritional supplementation on some aspects of behavior-associated with canine cognitive dysfunction24.
A nutraceutical supplement containing vitamin E, among others, improved canine short-term memory performance when assessed by the DNMP (delayed-non-matching-to-position) cognitive task48. In another study with aged beagles49, blood levels of vitamin E were correlated with cognitive improvement in canine neuropsychological tests.
Administration of a combination nutraceutical containing vitamin E lessened confusion and improved appetite in aged cats20.
Vitamins B1 and B12
Certain B vitamins, including thiamine (B1), and cobalamin (B12), are important for neurodevelopment and cognitive function50. The B vitamins are thought to serve roles in dogs and cats that are similar to their roles in humans1.
Thiamin pyrophosphate (TPP) is the major coenzymatic form of thiamin and is required for only a small number of enzymatic reactions. TPP is concentrated in neuronal cells and may affect chloride permeability by controlling the number of functional channels, possibly by phosphorylation51.
B12 (along with B6 and B9) serves as coenzyme in one-carbon metabolism. In this metabolism, a carbon unit from serine or glycine gets involved in a complex biosynthetic route where methionine is formed. A considerable proportion of methionine is then converted to S-adenosylmethionine (SAM), a universal methyl donor for numerous vital methylation reactions. Methionine synthesis is a most crucial part of the pathway for the health of brain tissue. In the brain, SAM dependent methylations are extensive, and the products of these reactions include neurotransmitters (catecholamines and indoleamines), phospholipids, and myelin50.
As mentioned previously, studies of cats14 and dogs15 revealed cognitive benefits for animals fed a diet supplemented with a blend of B vitamins, omega-3 fatty acids, antioxidants, and other nutrients. Because of the design of the studies, it could not be determined whether the B vitamins specifically contributed to the benefits.
Administration of a combination nutraceutical containing vitamin B1 and B12 lessened confusion and improved appetite in aged cats20.
The beneficial effects of higher baseline omega-3 fatty acid concentrations on certain cognitive and clinical outcomes of B vitamin treatment in older persons with Mild Cognitive Impairment, both cross-sectionally at the study end, and longitudinally for episodic memory, over the 2-year intervention period has been documented52.
Ginkgo biloba leaves extract – 24% Ginkgoflavonoids, 6% Total terpene lactones
Ginkgo biloba extract (GBE) is one of the most investigated herbal remedy for cognitive disorders and Alzheimer’s disease (AD). Standardized extract of Ginkgo biloba is a popular dietary supplement taken by the elderly population to improve memory and age-related loss of cognitive function. In a recent overview of reviews, there is clear evidence to support efficacy of GBEs for dementia, and the effect is dose and age-dependent53.
Ginkgo biloba extract (GBE) has an array of activities relevant to neurological functions while the antioxidant, anti-inflammatory, and neuroprotective effects are contributed mainly by the flavonoid and terpenoid content in GBE54.
Studies with EGb 76155 demonstrate several major actions56. it enhances cognition, improves blood rheology and tissue metabolism, and opposes the detrimental effects of ischaemia. Several mechanisms of action are useful in explaining how EGb 761 benefits patients with AD and other age-related, neurodegenerative disorders. In animals, EGb 761 possesses antioxidant and free radical-scavenging activities, it reverses age-related losses in brain alpha 1-adrenergic, 5-HT1A and muscarinic receptors, protects against ischemic neuronal death, preserves the function of the hippocampal mossy fiber system, increases hippocampal high-affinity choline uptake, inhibits the down-regulation of hippocampal glucocorticoid receptors, enhances neuronal plasticity, and counteracts the cognitive deficits that follow stress or traumatic brain injury.
In a recent study57, EGb761 treatment significantly improved the spatial learning and memory of rats. Moreover, EGb761 treatment could reduce hippocampal neuronal damage based on histopathological and ultrastructural observation, further supporting its neuroprotective action.
A nutraceutical supplement containing vitamin Ginkgo biloba extract, among others, improved canine short-term memory performance when assessed by the DNMP (delayed-non-matching-to-position) cognitive task48.
A study involving 22 aged dogs of different breeds with a nutritional supplement containing G. biloba L. leaves dry extract 40 mg, among others58, suggested, at the end of the treatment, a trend of improvement in behavioral task performance. Neuronal activity on primary cultured hippocampal neurons 21 days in vitro (DIV) was investigated by checking the level of cFOS, a functional marker of activity in cultured neurons, which was found to be increased.
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