Integrative Nutritional Therapy in Canine Cognitive Dysfunction

Canine cognitive dysfunction (CCD) is a progressive neurodegenerative condition that presents many of the behavioral and pathological changes seen in human Alzheimer’s dementia. It typically causes significant long-term suffering in both the patient and the caretaker. In patients with CCD and Alzheimer’s disease (AD), conventional dietary therapy has been helpful in preventing and slowing cognitive decline. Chinese medical food therapy to balance the body may also be beneficial in these patients. This paper will discuss conventional dietary intervention in dogs, along with traditional Chinese food therapy (CFT) according to pattern diagnosis in CCD. It is possible that a combination of syndrome differentiation in CFT and conventional nutritional therapy may help improve cognition and quality of life in patients with CCD.

Improvements in medicine and nutrition have led to an increased life span of canines. 1 As a result, there is an increased number of aged dogs with neurodegenerative disease. A syndrome, involving cognitive changes that are not associated with normal aging, occurs in dogs and shares many features of human dementia of the Alzheimer's type. 2 In the canine, the cognitive and pathological changes begin to develop in middle age and proceed as the dog ages, similar to the course of Alzheimer's disease (AD). 3 The syndrome is known as canine cognitive dysfunction (CCD), canine cognitive dysfunction syndrome, or canine counterpart of senile dementia of the Alzheimer's type (ccSDAT). 2,4,5 The original reports of this neurodegenerative disorder were published by Ruehl and colleagues in the mid-1990s. 6 In more recent research, evidence is accumulating that a similar condition may occur in cats. 6,7 The problem of canine cognitive dysfunction is significant, since 28% of 11-to 12-year-old dogs and 68% of 15-to 16-year-old dogs show one or more signs of the disorder. 8 It is also underdiagnosed in up to 85% of potentially affected companion dogs, causing unnecessary suffering. 9 In the literature, there is evidence that conventional nutritional therapy may be beneficial in improving cognition in canines. 10 Food therapy based on Bian Zheng or pattern diagnosis is one of the branches of traditional Chinese veterinary medicine (TCVM) that may be added to offer an integrated approach in the treatment of this disease. 11

PATHOLOGY
In conventional medicine, CCD includes the accumulation of amyloid-beta (Aβ) in the brain and cerebral vascular disease. 1,10,12 It is suggested that these processes are interconnected, with one leading to progression of the other. 10 According to Dewey et al., a combination of 4 pathological processes interact in the development of cognitive decline in both humans and dogs: 1) cerebral vascular hypoperfusion and associated impairment of mitochondria; 2) accumulation of toxic proteins, primarily Aβ; 3) oxidative injury in the brain; and 4) abnormal microglial and astrocyte activity that creates an environment of inflammation in the brain. 13 In affected dogs, loss of serotonergic, noradrenergic, and cholinergic neurons may be seen, along with cerebral atrophy and reduced oxidative glucose metabolism. 10,[14][15][16][17][18][19] A decreased concentration of vitamin E has also been found in the brain tissue of canines with ccSDAT. 5 It is becoming more evident that humans, dogs and cats show similarities in clinical progression and pathology associated with cognitive impairment. 20

CLINICAL SIGNS
The neurodegeneration in CCD leads to a gradual decline in cognitive function, evidenced by certain clinical signs. These include disorientation, poor social interaction, sleeping during the day/restlessness at night, house soiling, changes in activity, anxiety and loss of learned behavior/memory, represented by the acronym DISHAAL. 21 The decline has been reported by owners as changes in greeting behavior, staring into space or becoming lost in corners, loss of housetraining, pacing or vocalizing at night or newly developed behavior problems. 22 Studies have linked signs of cognitive dysfunction to Aβ deposition in certain regions in the canine brain. 23 The accumulation of Aβ in the frontal cortex along with frontal lobe atrophy is associated with loss of executive function. 24 In addition, maintenance behavior, such as eating, drinking and searching are affected. 23 In dogs with elevated prefrontal cortex Aβ, reversal learning deficits are seen. 6 The hippocampus is also susceptible to deposition of Aβ. 25 In hippocampal deficits, classic CCD signs are seen, with initial preservation of older memories, similar to early and middle stages of Alzheimer's disease.
In CCD, novel signs of fear, phobias and anxiety are commonly observed and may parallel the finding of agitation and anxiety in Alzheimer's dementia, where 20-60% of patients experience such issues. 20,26 Anxiety may be related to disturbances in the sleep-wake cycle seen in humans and dogs with cognitive impairment. Studies report that Alzheimer's patients with nighttime disturbances show higher levels of anxiety. 26

DIAGNOSIS
In CCD, the most noted clinical indications are alternations in daily routine and behavior. 2 As such, CCD is commonly diagnosed based on owner questionnaires and rating scales focusing on clinical signs. These problems are similar to those seen in the stages of Alzheimer's dementia. 27 A clinically relevant screening and assessment tool, the Canine Cognitive Dysfunction Rating Scale is effective in differentiating clinical signs of CCD from normal aging, with a diagnostic accuracy of 99.3%. 9 As an option, the Canine Dementia Scale can be used to identify mild and moderate cognitive impairment, and severe cognitive dysfunction. 28,29 In the assessment, diseases with similar clinical signs, such as primary behavioral conditions or other cerebral diseases need to be considered. 10,26 It may also be helpful to include neuropsychological tests and biomarker testing in differentiating dogs with CCD from normally aging dogs. The Vienna Canine Cognitive Battery provides a useful clinical tool to examine general, social, and physical cognition in pet dogs as well as interaction with humans. 30 A biomarker for early CCD detection in aging dogs is serum level of the neurofilament light chain, a central biomarker for neurodegeneration. 29

CONVENTIONAL TREATMENT
In CCD, conventional medications may help slow deterioration and/or improve clinical signs. Selegiline, a monoamine oxidase inhibitor with antioxidant properties, is reported to enhance dopamine and other catecholamines in the cortex, including the hippocampus. 20,31 Clinical signs associated with CCD have been alleviated with its use in both non-clinical and open-label field studies. 20,31,32 Side effects, however, can limit its usefulness and include anorexia, diarrhea, hindlimb paresis, ataxia and vestibular signs. 31,33 It may also interact with opioids, α-2 agonists, other monoamine oxidase inhibitors and medications that enhance serotonin transmission. 20,33 Propentofylline, a xanthine derivative, increases the molecular signal adenosine and is helpful in suppressing the release of microglial inflammatory mediators and free radicals. 34,35 It is used in treating dullness, lethargy and depression in CCD. 20,36 The minimal data on side effects includes increased body weight and decreased exploratory behavior in an animal model. 37 Nicergoline, an α-adrenergic antagonist, improves cerebral blood flow and metabolism, but there are limited clinical studies on its efficacy and safety in canines. 38,39 In a randomized experimental trial comparing the effects of propentofylline, nicergoline and adrafinil, only adrafinil, a noradrenergic agonist, showed efficacy in enhancing behavior in beagle dogs in open-field and home cage testing. 40 Adrafinil has also shown some efficacy in improving learning in dogs, but in a placebo-controlled crossover study, it was shown to significantly impair memory. 41 It is not generally seen to cause stereotypical side effects common to other stimulants. 40,42 Other therapies to be considered include gabapentin, N-acetyl-D-mannosamine and possibly a drug or natural therapy to improve cholinergic transmission. 20,43,44 Complementary conventional therapy may also be considered. As an example, benzodiazepines, such as lorazepam, may be helpful to treat disturbances in sleepwake cycle and anxiety due to the sedative and anxiolytic effects. 20,36,45 They are also helpful to treat fears and phobias. 33,36 In dogs, there is a concern for side effects, such as lethargy and idiosyncratic increase in activity or vocalization. 33,45

Modified Diets
In several studies, it is suggested that nutrition may have a beneficial effect in improving clinical signs and attenuating cognitive decline in CCD. 46 In a study assessing risk factors, it was demonstrated that dogs given a high-quality commercial diet intended for breed, life stage or health status were 2.8 times less likely to develop CCD than dogs given a general low-quality commercial food or table scraps. 46,47 Special diets, including supplements, designed to improve cognition may be helpful to include in a holistic treatment (Box 1).
Diets supplemented with the cellular antioxidants, vitamins C and E, mitochondrial cofactors (D,L-α-lipoic acid, L-carnitine), and a selection of fruits/vegetables rich in carotenoids and flavonoids may be used to alleviate cerebral neurodegeneration and improve cognition. 30,48,49 It is reported that carotenoids and flavonoids have antioxidant properties and may also act as mitochondrial cofactors. 13 In a longitudinal study, a diet containing these supplements was shown to lessen protein oxidation and Aβ in the brain in aged dogs. 48,49 This diet was also seen to significantly improve performance in oddity discrimination learning and size discrimination reversal learning in aged dogs as compared with a control diet. 50,51 Of interest, enhanced effects were seen in dogs that also received behavioral enrichment, consisting of social interaction, play, walking and cognitive testing. 20,48,49,51 In this study, canines given the supplemented diet showed an increase in serum vitamin E compared to control after 6 months. 50 In another study assessing the antioxidant diet, an improvement in performance on a landmark discrimination task was seen to correlate with serum vitamin E level in aged beagles. 52,53 The senior diet a based on antioxidants and mitochondrial cofactors may be helpful to lessen cognitive decline, especially if started at an early age, around 6 years. 20,30,54 A nutrient blend of antioxidants, B vitamins, fish oil and L-arginine may also help to prevent cognitive decline. In a non-clinical canine study, the diet significantly improved performance in learning tasks and reversal learning as compared to control. 55 The findings also showed a significantly higher plasma level of certain protective nutrients in the diet, including L-arginine, α-tocopherol, docosahexaenoic acid (DHA) and eicosapentaenoic acid. It is reported that L-arginine is a precursor of nitric oxide, a molecule that aids in memory formation. 55,56 It was concluded that long-term supplementation with these ingredients may help to maintain or enhance cognition in aged dogs.
In patients with CCD, dietary therapy has been shown to be helpful in improving clinical signs. In a double-blind placebo controlled clinical trial, a diet containing antioxidants, B vitamins, omega-3 fatty acids and 6.5% medium-chain triglyceride vegetable oil was effective in significantly improving all 6 categories of clinical signs, including disorientation, altered social interaction and loss of house training, after 90 days as compared with baseline in dogs with CCD. 57 The ingredients in this diet target some of the known risk factors associated with AD in humans, such as chronic oxidative stress, DHA deficiency and reduced cerebral glucose metabolism. 57 As a similar pathology is seen in dogs, a veterinary diet containing these ingredients b may help slow cognitive decline in patients suffering with CCD. 45,46 Additionally, a multicenter clinical trial assessed a diet enriched with carnitine, lipoic acid, long-chain omega-3 polyunsaturated fatty acids, vegetable-based carotenoids and vitamins C and E in dogs that were losing cognitive abilities. 58 This senior diet a showed significant improvements in behavior in supplemented dogs as compared with control. 10,53,58,59 Medium-chain triglycerides (MCTs) may be helpful to provide an alternate energy source for the brain. 20 In a non-clinical study, aged dogs given a 5.5% MCT supplemented diet c showed significantly improved performance in various cognitive tasks as compared with controls. 60 The dietary supplementation significantly improved visuospatial ability, attention, learning and reversal learning, with the more difficult tasks showing a more significant effect. In this study, dogs given the supplemented diet were also seen to have increased serum ketone levels, as MCTs are converted to ketones in the body. There were no adverse effects on the health of the aged dogs, and safety was confirmed in an independent study. It is suggested that MCT supplementation can improve cognition in aging dogs by providing an alternate source of energy for the brain in the form of ketones, without side effects. In the literature, it is reported that an MCT supplemented diet may also help improve cognition by increasing levels of n-3 polyunsaturated fatty acids in the brain, improving energy metabolism in mitochondria and lessening levels of the precursor of Aβ in the parietal cortex in aged dogs. 20,61,62 A diet containing botanic oils as a source of MCTs at 5.5% c,d , therefore, may be supportive in treating patients with CCD. 20,46,54

Nutritional Supplements
In CCD, nutritional supplements may also be supportive. S-adenosyl-L-methionine (SAMe), a molecule formed naturally in the body and found in all living cells, may be used as a supplement to help in the synthesis of neurotransmitters as well as glutathione, an endogenous antioxidant (Box 1). 20 In a double-blind placebocontrolled trial, SAMe as a dietary supplement resulted in a greater improvement in activity and awareness in dogs with cognitive dysfunction after 8 weeks. 63 In the mental impairment score, a significantly greater proportion of patients responded favorably to SAMe as compared with placebo (p = 0.0228). It was concluded that SAMe is safe and effective in improving signs of cognitive decline in aged dogs. In non-clinical controlled studies, SAMe has been shown to improve executive function in aged dogs as well as in the less cognitively impaired aged cats. 64,65 These findings support the use of SAMe in cognitive decline in aged dogs and cats, especially in early stages of CCD. As SAMe therapy may increase serotonin levels in the brain, it is used with caution when combining with serotonin-enhancing drugs. 20 A natural membrane phospholipid, phosphatidylserine, may be helpful to protect neurons and enhance acetylcholine release and neuron growth. [66][67][68] In a double-blind placebocontrolled trial, a supplement containing phosphatidylserine, antioxidants and omega-3 fatty acids e was effective in improving level of disorientation, change in interaction and loss of housetraining in canines with cognitive dysfunction within 21 days of treatment. 66 The overall assessment by investigators showed a significant difference in age-related behavior and quality of life favoring nutritional therapy (p = 0.008 and p = 0.004, respectively). These data support the clinical practice of nutrient supplementation in patients with CCD. It is reported that a supplement containing phosphatidylserine, Ginkgo biloba, vitamin E and pyridoxine f may also benefit cognition in canines. 69 In a blinded crossover study in aged dogs, performance accuracy in a delayednon-matching-to-position (DNMP) memory task was significantly improved in treated dogs as compared with control. The effect was maintained for 70 days posttreatment, suggesting a long-term benefit in improving memory. In an open-label pilot study, use of this supplement also showed a significant improvement in clinical signs in dogs with CCD. 67 The herb Ginkgo biloba is reported to stimulate acetylcholine release and lessen oxidative stress and Aβ in the brain. 46,69,70 Pyridoxine (vitamin B6) is helpful, as it is a cofactor in neurotransmitter synthesis. 46,69 A calcium binding protein, apoaequorin, acquired from the jellyfish (Aequorea victoria), may provide some neuroprotection. 71 It is reported that this protein helps protect hippocampal neurons from excitotoxicity and cell injury in ischemia. 10,71,72 Interestingly, a decrease in endogenous calcium binding proteins is noted in aging and Alzheimer's disease. 71 In a non-clinical study, apoaequorin therapy was seen to improve object discrimination learning and selective attention as compared with selegiline and placebo controls in aged beagle dogs. 72 It has also shown cognitive benefits in aging humans with memory impairment. 73 In non-clinical laboratory studies, no adverse effects were noted. 71,72 Additional ingredients mentioned in the literature that may help patients with CCD include resveratrol and curcumin. 10 A component of resveratrol, miyabenol C, isolated from the stems and leaves of the small-leaf grape, may lessen Aβ in the brain. 74 Curcumin, a phenolic compound found in the rhizome of the turmeric plant Jiang Huang (Curcuma), may pass through the blood-brain barrier and bind to Aβ in the brain, inhibiting its aggregation and fibril formation. 75,76 In animal models, resveratrol and curcumin have been shown to improve memory. 77,78

Nutritional Supplements with Calming Effects
Natural conventional therapies may also be useful in alleviating signs of anxiety and sleep-wake disturbances in CCD (Box 1). 20 Alpha-casozepine, a decapeptide derived from α S1-casein in milk, has been studied for efficacy in treating anxiety in cats and dogs. 36,45 It is structurally similar to gamma-aminobutyric acid (GABA), with an affinity for benzodiazepine receptors. 45,79 In a multi-center randomized controlled trial from Europe, alpha-casozepine g was seen to significantly decrease the emotional disorders evaluation in dogs (EDED), a scale measuring phobias and anxiety-related disorders. 79 There was, however, no significant difference as compared with selegiline as a control. It was concluded that alphacasozepine is safe and effective in the management of anxiety in dogs. In a similar multi-center study in cats, alpha-casozepine showed a statistically significant difference as compared with placebo in management of social phobias, such as fear of strangers and contact with familiars. 80 L-theanine has also been shown to decrease anxiety in companion animals. Studies suggest that L-theanine may increase central serotonin, dopamine, and GABA levels and have neuroprotective effects. 81,82 In an openlabel trial, therapy with an L-theanine-based supplement h was seen to significantly decrease global anxiety and diminish specific behaviors, such as panting and pacing, in storm-sensitive dogs. 83 In a non-clinical study in dogs, this supplement was shown to be effective in increasing human interaction and approach as compared with placebo. 84 L-theanine has also demonstrated efficacy in helping to manage stress-related behavior in cats. 81 A combination of souroubea and platanus may be helpful in lessening anxiety levels in dogs as well. The plant extracts contain pentacyclic triterpenes that are known to have anxiolytic, anti-depressant and anti-inflammatory effects. 85 In vivo studies indicate that the extract of Souroubea sympetala acts at the GABA A -benzodiazepine receptor to elicit its anxiolytic effect. 86 In a non-clinical study in beagle dogs, a dietary supplement containing a mixture of Souroubea spp. vine and Platanus spp. bark i was significantly more effective than placebo in decreasing anxiety response to intermittent thunder sounds and serum cortisol levels in a dose-dependent manner. 85,87,88 Other natural products that may help with anxiety and sleep disturbance in CCD include melatonin, valerian root (Valeriana officinalis) or a multi-ingredient veterinary product j containing L-theanine, whey protein, Magnolia officinalis and Phellodendron amurense. 10,20,36,54,89,90 Certain platanus, magnolia and phellodendron species have been used for centuries as Chinese herbal medicines (CHM). [91][92][93] 95 The principles and many of the herbs used by Shiduo Chen remain in TCM and TCVM treatment of cognitive dysfunction through the present day. 100,101 The classic Chinese literature also references the use of acupuncture and moxibustion in treating cognitive decline. In a review on acupuncture therapy for dementia recorded in 93 ancient books, common acupoints were identified (Table 1). 102 In the treatment of dementia, ancient practitioners used acupuncture therapy to regulate Qi. In Qiong Yao Shen Shu (Fine Jade Devine Book) written in the Song Dynasty, Shen-men (HT-7) and Zu-san-li (ST-36) were suggested treatments. 102,103 The acupoint Shen-men (HT-7) is the Yuan-source point of the Heart Meridian, where the Heart Qi is said to enter and exit. 102 In the Ming Dynasty clinical text Yi Xue Gang Mu (Systematic Medical Studies), acupuncture at Shen-men (HT-7) and Hou-xi (SI-3) was recommended. 102 The acupoint Hou-xi (SI-3), as the opening point of the Governing Vessel Meridian, is said to clear the Mind. 104 The ancient Chinese also selected the Jing-well acupoints to open the orifices and awaken the brain. 102 In the Zhen Fang Liu Ji (Six Collections of Acupuncture Prescriptions), Wu Kun proposed using moxibustion cones at Shao-shang (LU-11) and Yin-bai (SP-1). In cases of dementia due to Qi-Blood Deficiency, moxibustion was performed at Guan-yuan (CV-4) to nourish Qi and Blood. 102 In the classical work Bian Que Xin Shu (Book of Bian Que's Mind, 1146 C.E.), using moxibustion cones at Guan-yuan (CV-4) was suggested for mental disturbance due to Heart Blood Deficiency. This acupoint has a calming effect on the Mind. 104 The ancient Chinese knowledge and techniques described still apply in TCM and TCVM treatment of cognitive decline in modern clinical practice. 105

Chinese Medical Theory for Canine Cognitive Dysfunction
In Chinese medical theory, the Shen or Spirit is housed in the Heart and is associated with mental clarity, memory and sleep. 100,106 The substances of the Heart are essential to mental activity and brain function, thus a Deficiency of Heart Qi or Yin-Blood creates loss of Shen and affects cognitive abilities. Additionally, there is a close relationship between the Heart and Kidney and cognition. 11 The Kidney Jing nourishes the brain while the Heart balances its activity. It is possible to see a decline in cognition with a Deficiency of Kidney Jing. In the Chinese medical paradigm, the Spleen is also involved in cognitive ability, as it provides the movement of fluids. 95,100,106 A Deficiency of Spleen Qi causes accumulation of fluids and generation of non-substantial Phlegm that is said to mist the Mind and obstruct the Shen. As Aβ plaques in the brain are considered Phlegm or local Blood Stagnation, this pathological buildup obstructs the flow of Qi and impedes neuronal transmission, affecting cognitive function.

Source Action/Indication Acupoints
Review -93 ancient books 102 Common acupoints for dementia In TCVM, the Deficiency patterns seen in CCD may include Heart and Spleen Qi Deficiency, Heart Yin-Blood Deficiency, and Kidney Jing Deficiency, while the Excess patterns are Phlegm or Phlegm Fire Misting the Mind, Qi-Blood Stagnation and Liver Qi Stagnation (Table 2). 11,100,106 These imbalances in the body are addressed with TCM treatment principles of tonify Spleen Qi to support Heart Qi, tonify Heart Qi to support the Shen and tonify Heart Yin-Blood. 11,100 In addition, treatment principles to address Excess include dispel Phlegm to remove obstruction of Shen, clear Fire, resolve Qi-Blood Stagnation and soothe Liver Qi. In TCM theory, Kidney Jing declines with aging and since it is the origin of Kidney Yin and Kidney Yang, a Deficiency of these may also be present. 11 It is important to treat Kidney Jing Deficiency in these geriatric patients by nourishing Jing, nourishing Kidney Yin or warming Kidney Yang, and tonifying Spleen to support Post-natal Jing.

Clinical Studies
In current veterinary literature, 2 clinical trials and a case report describe the use of CHM to treat signs of CCD. One is a randomized double-blind controlled study by Hielm-Bjorkman et al. assessing the effect of Panax ginseng in combination with brewers' yeast in older dogs with geriatric clinical signs. 107 In this study, the efficacy was measured with questionnaires and visual analogue scales (VAS). At the end of an 8-week study period, dogs given Panax ginseng significantly improved in comparison with a brewers' yeast control in 4 of 7 mental variables: alertness-interest in surroundings, forgetfulness, alertness VAS and quality of life VAS. There were no side effects reported during the study period. It was concluded that Panax ginseng plus yeast is more effective than yeast alone in improving quality of life. This study is of interest, as Panax ginseng has been used as a tonic in traditional CHM for thousands of years. 108 The ginseng root contains numerous ginsenosides that are likely to be the active ingredients. 107 Effects have been associated with the ginsenoside Rb1, a neuroprotective molecule that has been shown to increase neural proliferation and differentiation of progenitor cells in the dentate gyrus of the hippocampus. 107 In China, extracts from the leaves of Ginkgo biloba have also been used therapeutically for centuries. 109 It is reported that the Ginkgo leaf extract contains terpene lactones and flavonoids that may help support cerebral blood circulation. 38 In an open 8-week clinical trial, Reichling et al. assessed the efficacy of Ginkgo leaf extract in reducing behavioral disturbances in elderly dogs with cognitive decline. 38 It is reported that 5 of 6 protocol-determined clinical signs were significantly improved: disorientation, sleep and activity changes, behavioral changes, general behavior and general physical condition. The overall severity of the geriatric condition in the patients was significantly reduced, with a positive effect apparent at 4 weeks (p = 0.0002). In this study, 15 (36%) of the patients were free of clinical signs at the end of the treatment period, and overall efficacy was good or very good in 79% of the dogs, as determined by the investigator. No serious side effects related to the Ginkgo extract were seen. The study concluded that Ginkgo leaf extract as a dietary supplement appears to be safe and effective in the treatment of elderly dogs with cognitive decline and may increase their quality of life. 38 In a case report by Fowler, a geriatric dog with clinical signs of Shen Disturbance was successfully treated with CHM. 110 The 14-year-old spayed female mixed breed dog with a Water constitution was experiencing severe anxiety, disorientation, inability to sleep and anorexia. The patient had received selegiline, valerian root extract, melatonin, acepromazine and Rescue Remedy k , without a clinical response. An inadequate response was seen to fluoxetine and benzodiazepines. In the TCVM exam, signs of cognitive dysfunction, diminished Shen, extreme anxiety and mild to moderate fear were present. A clear TCVM Pattern was not apparent, and the patient was treated with the Chinese herbal medicines, Er Yin Jian combined with Stasis in the Mansion of the Mind l . The Chinese herbal formula, Er Yin Jian, may be helpful in behavioral disturbance without a clear Zang-fu organ pattern. Stasis in the Mansion of the Mind l is indicated for treatment of cognitive dysfunction. 111 In this patient, an improvement was seen within 2 weeks, including sleeping soundly at night, showing interest in surroundings and family, a return of normal appetite and discontinuance of hiding and obsessive-compulsive behaviors. The patient was well maintained on the 2 CHM formulas. The clinical findings from this case and the 2 clinical trials suggest that CHM may be beneficial in treating signs of CCD. It is interesting that some of the Chinese herbs used, such as ginseng and ginkgo, may also be considered as foods. 11,112,113

TRADITIONAL CHINESE VETERINARY MEDICINE FOOD THERAPY
In Chinese medicine a diagnosis is made based on Bian Zheng, a system of TCM/TCVM Pattern differentiation. 114 The method of Bian Zheng is based on determining a patient's pattern using Si Zhen (the Four exams). 11,114 In CCD, most patients present with a Deficiency Pattern due to the progressive nature of the disorder. 11 A pathogenic factor, however, may also be present. According to Koh, the Root is commonly associated with a Deficiency, and the Manifestation with an Excess. 11 It is suggested to resolve the Excess first if it is caused by the Root pattern to prevent further pathological change. Otherwise, the Deficiency is treated first or they may be treated together.
In TCVM, the treatment of CCD combines acupuncture, CHM, Tui-na and food therapy. This approach may be effective as a sole therapy or combined with conventional medicine for integrative treatment of these patients. 11 In ancient Chinese texts, it is said that food therapy is helpful in balancing the body. In Plain Questions: On Soup and Mash, written more than 2000 years ago, it states that grains boiled for a time and made into mash will nourish the Zang organs. 113 A section in Plain Questions also describes the distribution of the five flavors of food. Bitter food is said to be associated with the Heart and Spirit (Shen) and may be helpful in CCD patients: asparagus, cauliflower, broccoli, kale, bitter melon, amaranth (slightly bitter), parsley, ginkgo, and apple cider or Chinese fermented vinegar. 11,91,100,112,113 In this work, salty foods are said to benefit the Kidney: salmon, clam, crab, mussel, oyster, abalone, anchovy, sardines, seaweed, kelp, alfalfa sprouts, tofu, barley, millet, chia seed and parsley. 11,91,100,112,113 Sweet foods will benefit the Spleen: pumpkin, sweet potato, yam, shiitake mushroom, oats, black sesame seed, ginseng and honey. 91,100,112,113 It may be helpful to add kidney beans or black beans to benefit the Kidney as well as strawberries or blueberries to provide antioxidants. 11

Heart and Spleen Qi Deficiency
In the pattern of Heart and Spleen Qi Deficiency, a diagnosis is based on signs of progressive cognitive decline with depression of the Shen. 11 If Heart Qi is deficient, the Shen will be depressed and the spirit is lost. 112 If the Spleen is also affected, fatigue and depression worsen. Some clinical signs are sleeping more, lessened social interaction/responsiveness, quietness and fearfulness. 11,112 The patient may have decreased appetite, weakness, a desire to lie down and panting due to shortness of breath, with clinical signs worse during the day (Yang time). 11,104,115 It is possible to see loss of housetraining or other learned behaviors, poor memory and inability to recognize family/friends as the disease progresses. 11,100 In a TCVM exam, the tongue is pale and wet, possibly with a white coating. 11,112 The pulse is deep and weaker on the right, particularly in the Spleen position. 11,100 Treatment principles are tonify Heart and Spleen Qi and calm the Shen. 11 In this pattern, the aim of food therapy is to tonify Qi, so neutral and warming foods are used. 100 Foods to tonify Spleen Qi include carrot, pumpkin, winter squash (acorn, butternut) and sweet potato (Table 2). 11,100,112 Foods that tonify both Heart and Spleen Qi include salmon, chicken egg yolk, chickpeas and pecan. 112 Cardamom and ginger warm the Middle Jiao (Zhong Jiao) and will benefit the Spleen. Foods with heavy mineral content, such as chicken eggshell, calm the Shen. It is recommended to avoid Cold or raw foods and Damp engendering foods such as dairy, saturated fats and dry processed foods. 11,100,112

Heart Yin and Blood Deficiency
A diagnosis of Heart Yin and Blood Deficiency is based on signs of progressive cognitive decline along with increasing anxiety and restlessness at night. 11,100,112 It is said that Heart Yin and Blood nourish the Shen. 115 In a Deficiency of these substances, the Shen will not be nourished or calm. 112,115 Some signs are less responsiveness, listlessness, loss of housetraining and poor memory. 11,112 In the evening there may be pacing, barking, sleeping poorly or staying awake at night. It is said that clinical signs are worse in the evening (Yin time). It is possible to see cool-seeking behavior and other Warm signs due to Yin Deficiency, yet the coolness of Blood Deficiency may lessen their appearance. 100 The patient may have signs of dryness, such as dry skin, pads and nails. 112 In the TCVM exam, the tongue is dry, red or pale, with crack lines and little coating. 11,112 The pulse is deep, thin and weak, especially on the left. Treatment principles are nourish Heart Yin and Blood and calm the Shen.
In this case, the aim of food therapy is to nourish Heart Yin and Blood. A few foods to nourish Heart Yin include chicken egg white, yogurt, mung bean and lima bean ( Table 2). 112 It is recommended to avoid foods with a Hot or Yang energy and dry food, as it is heating and may contribute to Yin-Blood Deficiency. 100,112 In addition, foods to nourish Heart Blood may be given, e.g. tuna, beets, lima beans and dates. 112 Yin and Blood tonics in general are also used. 11,100,112 Omega-3 fatty acids found in fish oil and krill oil are considered to be Yin and Blood tonics. 112

Kidney Jing Deficiency
Kidney Jing declines in aging animals, and a deficiency may be seen in geriatric patients with CCD. 11 In these patients, serial exams are needed, as a Deficiency of Kidney Yin or Yang may arise and will need distinct foods as therapy. 11,100 In chronic patterns, long-term injury to Kidney Yin may result in depletion of Kidney Yang and vice versa, as these are mutually dependent. 11 A pale tongue, weak pulse and signs of Qi Deficiency reflect a Deficiency of Kidney Jing. 100,112,115 Treatment principles are nourish Kidney Jing, nourish Kidney Yin or warm Kidney Yang, tonify Spleen to support post-natal Jing and support the Water element. 11,112 Food therapy is given according to the presenting deficiencies.
In Deficiency of Kidney Jing, the aim is to supplement with foods that nourish Jing, e.g. foods that "start life" (seeds, eggs, nuts), sea cucumber, alfalfa and artichoke leaves ( Table 2). 112 It is recommended to avoid an abundance of Cold or raw foods. 112 It is also helpful to offer foods and supplements to nourish post-natal Jing, e.g. salmon, yams, kidney beans and black beans. 112 Spleen Qi tonics, especially those that benefit or enter the Kidney Channel, are used. It is recommended to avoid highly processed dry foods, as these foods provide little nourishment for post-natal Jing. 112 It is beneficial to support the Water element and Jing using salty foods, such as kelp and seaweed, and dark foods, such as black-eyed peas, black beans, blackberries and black sesame seeds. 112 In Yin Deficiency, a diagnosis is based on signs of progressive decline in cognition along with clinical signs of Heat and hind end weakness or lumbar pain. 11,112,115 A Deficiency of Yin is described as the inflammatory component of CCD. 13 It is possible to see poor memory, restlessness, evening anxiety and difficulty falling asleep at night. 11,112 There may also be signs of dryness. 112 Heat signs may include panting, drinking small amounts of water frequently, cool or shade seeking and warm ears and/or paws. 11,112 The clinical signs are worse in late evening or at night (Yin time). In the exam, a red or deep red and dry tongue with crack lines and little to no coating may be seen. The pulse is fast, deep, thin and weaker on the left.
If Yin Deficiency is present, the intent is to clear False Heat and nourish Kidney Yin. 100 Yin tonics that are cooling, moistening and replenish Body Fluids are given. 112 Some cooling foods that tonify Kidney Yin are scallop, clam, asparagus and seaweed ( Table 2). 112 A few cooling foods to replenish Body Fluids include asparagus, spinach, lemon and pear. Fish oil is considered a Cool Yin tonic. It is recommended to avoid Hot or Yang foods, highly refined foods/carbohydrates, and dry food. 11,112 In patients with Yin Deficiency, it is suggested to avoid giving cold food or ice cold water, as this decreases stomach acid, impairs digestion and engenders Dampness/Phlegm. 112 In Yang Deficiency, a patient may present with signs of Cold, extreme weakness in rear limbs or back, and lumbar pain. 11,112,115 There may be lethargy, depression and hypersomnia, along with decreased appetite, early morning diarrhea and urinary or fecal incontinence. 11,112 Cold signs may include aversion to cold, warm/heat seeking, and cool to cold ears, back and extremities. 11,112,115 In the TCVM exam, the tongue may be pale to lavender, wet and swollen. The pulse is slow, deep and weak, especially on the right in the Kidney position.
If Yang Deficiency is present, foods that clear False Cold and tonify Kidney Yang are given, e.g. shrimp, prawns, milk (goat/sheep) and pistachio (Table 2). 11,91,112 As Deficiency of Yang affects the Spleen, foods that warm the Spleen are helpful in draining Dampness. 112 Yang tonics are usually sweet to nourish the Spleen and pungent to disperse Stagnation created by Cold in the Channels. It is recommended to avoid Cold or raw foods, cold water intake, and added salt, as it may increase water intake and exacerbate the condition. 11,112 Excess Patterns

Phlegm Misting the Mind
In Phlegm Misting the Mind, the patient may have an underlying Deficiency of Spleen Qi, with increased Dampness due to inability to move fluids. 11 In this case, non-substantial Phlegm may be created and enter the Channel connecting the Heart with its orifice, causing obstruction of the Shen. 100,115 Some signs include mental confusion/depression, lethargy, a change in voice, vomiting of phlegm and dull eyes. 11,104 It is also possible to see other signs of Spleen Qi Deficiency. 112 In the TCVM exam, the tongue is pale and wet with a thick coating and may be swollen with a midline crack extending to the tip. 11,104,112 The pulse is slippery, possibly reflecting Dampness. The treatment principle is transform Phlegm and open the orifices of the Heart. 11 In this pattern, supplementing with foods to transform Phlegm is suggested, e.g. shrimp, mustard greens, radish and daikon (Table 2). 11,100,112 Conventional herbs to transform Phlegm include peppermint leaves, thyme and watercress. 112 It is helpful to use foods to tonify Spleen Qi in these patients. It is recommended to avoid foods that create Dampness such as dairy or peanut butter, Cold or raw foods and dry highly processed pet foods. 112

Phlegm Fire Misting the Mind
In this pattern, there is obstruction of the orifice of the Heart and misting of the Mind by Phlegm and Fire. 104 A diagnosis is based on signs of Heat in combination with the clinical signs of Phlegm Misting the Mind. The signs include manic or strange behavior such as tail chasing or sudden severe outbursts, irritability, aggressiveness and restlessness. 11,104,112 It is also possible to see mental depression and dullness. 11,104 Heat signs include increased thirst, cool seeking, and warm ears, back and paws. 11,100 The tongue is red to deep red, possibly with a yellow coating and/or swollen, and the tip may be redder or have red points. 11,104,112 The pulse is fast, full and slippery if Damp is present. 11,112 The treatment principles are transform Phlegm, clear Fire and calm Shen. 11,112 The aim of food therapy is to provide supportive treatment to transform Phlegm and clear Fire (e.g. bamboo sprouts, daikon, seaweed and kelp) [ Table 2]. 11,100,112 Yin tonics, such as lemon and pear, protect the Heart Yin from damage due to Fire. 112 It is said that foods with bitter taste benefit the Heart and are helpful to drain Dampness. It is recommended to avoid Hot or Yang foods, Damp engendering foods such as dairy or oily food, and dry highly processed pet food, as it creates Dampness and Heat. 11,91,100,112

Qi-Blood Stagnation
As Qi is needed to move Blood and Blood is needed to carry Qi, a Deficiency of either may cause Qi and Blood to become Stagnant in the Brain and affect cognition. 100 This correlates to the microvascular pathology seen in CCD. 13 Some signs are sleeping less, lessened social interaction/responsiveness and irritability. 11,104,115 It is possible to see loss of housetraining or other learned behaviors, getting lost in corners and wandering in the home. 11 The patient may also have weakness and coolness in limbs. In the exam, the tongue may be pale purple or purple on the sides. Pulses may be wiry in Qi Stagnation or choppy in Blood Stagnation. 11,112 The treatment principles are move Heart Qi and Blood, resolve Stagnation, and open the orifices of the Heart. 11 In this case, it is helpful to include foods to move stagnant Qi and Blood, e.g. shrimp, crab, mustard greens and kale (Table 2). 11,100,112 The sweet and pungent tastes stimulate the circulation of Qi and Blood. 112 It is recommended to avoid foods that create Dampness, such as dairy, and diets with an overall Hot energy. 112

Liver Qi Stagnation
The Liver controls healthy Qi flow and mental state. 115 A stagnation of Liver Qi may transform into Fire and disturb the Shen. It may also interfere with the activity of the Spleen and digestion. A patient may present with irritability, aggressiveness, fluctuation in mental state, depression and pain or distension in the hypochondrium. 11,104,112,115 It is also possible to see nausea, vomiting, diarrhea or constipation and a decreased appetite, possibly reflecting interference with the Spleen. 11,115 Heat signs may include increased thirst and conjunctival redness. 11,104,112 In the exam, the tongue may be pink to red or lavender and may have strawberry dots on the sides if there is Liver Heat. 11,104,112 The pulse is wiry, particularly on the left. 11,104 The treatment principles are soothe Liver Qi, strengthen Spleen and Stomach, and calm Shen. 11,112 It is helpful to supplement with items to soothe Liver Qi, e.g. spinach, dandelion greens, celery and carrots (Table 2). 11,112 Foods to circulate Qi-Blood, such as peppermint leaves and vinegar, are helpful. 112 It is said that green foods and sour foods will benefit the Liver. 112,113 It is recommended to avoid foods that create Dampness e.g. dairy, excess fats and processed foods, Hot or Yang foods, and feeding a large meal, as this may add to Stagnation and Heat. 112

CONSIDERATIONS -HUMAN LITERATURE
In humans, certain dietary patterns may lessen the risk and progression of cognitive decline. It is reported that a diet containing fruits and vegetables, nuts, whole grains, fish, omega-3 fatty acids, probiotics, soybeans and MCTs, may be beneficial. 10,54,[116][117][118] A three-city cohort study conducted in France showed that a diet including fruits and vegetables consumed daily may decrease the risk of dementia in humans. 119 The study also found that frequent intake of fish and omega-3 rich oils may lessen the risk of AD and dementia, particularly in non-carriers of the ApoE ε4 allele, a risk factor of late-onset AD. In another study, the benefit of vitamin C in fruits and vegetables, as well as vitamin E in grains, nuts and other foods has been described. 120 This study determined that a high intake of vitamin C and vitamin E in foods may be associated with a lower risk of incident AD. In some studies, red meat, refined sugar, saturated fats and highfat dairy foods are noted as detrimental to cognition. [116][117][118] As the pathology is similar in CCD and AD, the findings in these studies are consistent with the idea that dietary patterns may be helpful in lessening the risk and progression of cognitive decline in dogs. 10 It is possible that specific dietary patterns may help in preventing cognitive decline by influencing the composition of bacteria in the gastrointestinal system. 121,122 In humans, a diet including high level consumption of fruits, vegetables, legumes and cereals may have antiinflammatory effects in association with microbiome alterations. 122,123 The alterations in phyla may also lead to an increase in intestinal short chain fatty acid (SCFA) levels. 122,124 These bacterial metabolites are helpful to stimulate the release of serotonin, causing a positive effect on learning and memory, and also interfere with accumulation of Aβ. 89,121,125,126 In one human study, measures of cognitive function were also improved. 122 From a Chinese medical viewpoint, the aim of food therapy is to prevent disease, remove illness and slow aging. 113 In China, there is a long history of gerontology, with early monographs on health in aging. 127 In the Yang Lao Shi Liao (Medical Diet on Health Preservation for the Aged), written by Sun Simiao in approximately 680 C.E., it is said that using Niu Ru (milk), Hei Zhi Ma (black sesame) and Feng Mi (honey) in the elderly may lead to longevity. It is recommended that milk and honey be ingested warm and a little at a time. Hei Zhi Ma (black sesame) is said to nourish Jing, Yin and Blood and may benefit Kidney Jing and Yin Deficiency or Heart Yin-Blood Deficiency in CCD. 91,100 It is known that black sesame contains lecithin and vitamin E that may help to maintain normal function of the brain and delay cell aging, respectively. 127 Honey is said to supplement the middle and may help in the movement of fluids. In a recent study, spicy food that has a pungent taste is also reported to benefit cognition. 128 In Chinese medical theory, foods with a pungent taste are said to promote the flow of Qi and Blood and may be helpful in resolving Qi-Blood Stagnation. 91,129

INTEGRATING EAST AND WEST
It is possible that integrative dietary therapy may be the most helpful in cognitive decline. A recent paper reported that an increase in efficacy is found when combining Chinese food therapy (CFT) with conventional nutritional therapy in human studies. 129 As an example, Shen et al. found that foods with a Cold nature and high in potassium, magnesium, calcium and fiber were more effective in treating hypertension in patients with Yin Deficiency. 129,130 It is interesting to note that many foods shown to lessen cognitive decline in humans have a neutral to Cold nature and may benefit patients with a Deficiency of Yin. 13 According to Dewey et al., many canine patients with CCD show this pattern. 13 It is possible with consideration of the extensive information in human literature, both ancient and modern, that a combination of syndrome differentiation in CFT and conventional nutritional therapy may help improve cognition and quality of life in canines with CCD.
In the literature, there is accumulating evidence that dietary therapy may be helpful to prevent or slow cognitive decline in canines. 13 The nutritional supplements that demonstrate efficacy, such as SAMe, may be added to a conventional diet or a CFT plan. In CFT, antioxidants, MCTs and other enrichment may be included in the diet, with consideration of the Bian Zheng, the TCVM Pattern of the patient. The fat sources may include fish oil, a Yin Table 3: Calculated metabolizable energy (ME) for average elderly dog with potential amounts of coconut oil that can be used to help with canine cognitive dysfunction by providing a source of medium-chain triglycerides. It is recommended to use coconut oil conservatively, especially if treats are given. The extra calories are meant to replace some of the calories consumed in the diet. 10 Dog weight (kg) ME (kcal) m 10% ME Coconut oil  tonic with a Cool energy, and coconut oil, considered as neutral to cool in Chinese medicine. Coconut oil may be used as a source of MCTs to supplement a diet in dogs at approximately 1-1.5 teaspoons per 10 lbs. of body weight (Table 3). 10,13 An example of a CFT diet with a cooling protein and carbohydrate source is provided ( Table 4). As clients are likely to consider dietary therapy, it is a useful option that may benefit cognition in canine patients.

SUMMARY
There is a growing body of literature demonstrating the importance of nutritional therapy when treating cognitive disorders in the dog. Modified diets and nutritional supplements rich in factors that support the nervous system such as antioxidants, MCTs and vitamins address neurodegenerative pathology associated with canine cognitive dysfunction. Traditional Chinese medicine has been used for centuries to treat cognitive decline and may be integrated with conventional nutritional therapy or used as a sole treatment. Chinese food therapy is based on diagnosis of a disease pattern of imbalance. Selection of foods that treat pattern deficiencies or excesses associated with CCD are then used to make up a balanced diet to treat the unique pattern observed in a patient. Integrative dietary therapy in CCD provides clinicians with a personalized treatment to help improve cognition and quality of life in their canine patients.