Canine Cognitive Dysfunction CDS

As our wonderful companions reach their golden years, their behavior may change and become afflicted with canine cognitive dysfunction which is similar to Alzheimer's disease in humans. Canine Cognitive Dysfunction Syndrome is NOT A NORMAL AGING PROCESS FOR A SENIOR OR GERIATRIC DOG! Only recently has it been given a name. Anipryl was approved by the FDA in 1999 for treatment. The generic version SELEGILINE was used for Parkinson's Disease.

Vivitonin is another medication sold overseas (if you click on the name Vivitonin it will take you to the pharmacy). It supplies more blood to the brain. The description of Vivitonin is "For the improvement of dullness, lethargy and improvement in overall demeanour in older dogs.". You don't need a prescription from this pharmacy.
I have not found research to distinquish between the effects of a mild stroke and some signs of cognitive canine dysfunction. My vet said that strokes are rare in dogs. Thank goodness for wonderful vets. Although a California study found the rate( at least one symptom) very high for canine cognitive dysfunction syndrome in senior dogs, my vet who is located in Manhattan New York and who has been practicing for over 25 years said that only ten to at most twenty percent of his senior dogs have gotten CDS. He is a superior diagnostician and asks a lot of questions besides giving a thorough examination.

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The signs of canine cognitive dysfunction syndrome or "old dog syndrome" commonly seen in dogs are:
  • lose of house training
  • increased barking or whining
  • increased anxiety or fear signs
  • disorientation-appearing lost or confused,getting stuck behind furniture or in corners, walking in circles, becoming forgetful,walking aimlessly,staring into space, repetitious or compulsive behavior
  • change in sleep patterns-up at night, sleep all day
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  • lack of responsiveness
  • other changes,may not recognize you, their name,may become more docile, more aggressive.. You can liken it to human senility. An article at the petcenter says "CDS is not "normal aging". A number of pathophysiological changes are suspected to play a role in its development. These include:
    * deposition of amyloid plaques in the cerebral cortex and hippocampal part of the brain
    * alterations in neurotransmitters, including dopamine
    * increased levels of monoamine oxidase B (MAOB) in the brain
    * increased levels of free radicals
    L-DEPRENYL HYDROCHLORIDE SELEGILINE HYDROCHLORIDE,BRAND NAME: ANIPRYL OR ELDEPRYL is used to help treat canine cognitive dysfunction by increasing brain concentrations of the neurotransmitter dopamine. Hopefully you can see a difference in a month or so. If you don't see a difference in the first month, your vet might tell you to try two pills a day for the next month. ANIPRYL doesn't work for all dogs. A great writeup on L-DEPRENYL can be found at http://www.petsinfo.org/elderlydogs1.html. "One third of canine CD patients respond extremely well to treatment with deprenyl by regaining their youthful vigor; another one third respond reasonably well; and one third do not respond at all (perhaps there is a variant of CD with different neuropathology). The bottom line is that for any dog that is slowing down to the point that problems become apparent, treatment with deprenyl is the logical route once other organic causes for reduced mental function have been ruled out.
    Here is a write up on selegline
    " Selegiline has immune-system-boosting and anti-neurodegenerative effects. .... Taken consistently in low doses, selegiline tends to extend the life-expectancy of rats by some 20%; enhances drive, libido and endurance; and independently improves cognitive performance in Alzheimer's patients and in some healthy normals. It is used successfully to treat canine cognitive dysfunction syndrome (CDS) in dogs...Selegiline protects the brain's dopamine cells from oxidative stress.

    Lori's Baby

    A member of the canine cognitive dysfunction group on yahoo wrote some helpful suggestions:

    Baby is 16 years old(whippet) and I took some of her issues as normal signs of aging until she started the pacing, staring at walls or the wrong side of the door, ...you know the stuff. I found this article (http://holisticvetpetcare.com/cognitive- dysfunction-syndrome.htm ) and although I don't really buy into the entire treatment I thought it does make sense to remove some of the toxins from her diet. I switched her to organic food and only filtered or distilled water. I also added extra B vitamins to her diet (B vitamin's are supposed to effect the nervous system). When the pacing got to be too much or a thunderstorm was approaching I gave her a Pet-ez which is a natural sedative which just calms her, it doesn't make her drowsy. The results have been remarkable, after several months she started becoming her old self again. Now she eats all her food, plays, runs and even tolerates other dogs (she started being aggressive towards other dogs which is odd because she always had a large group of dog friends). She's a much happier pup.
    Also, I have always found that it is much easier to give a dog a pill if you drag it through some peanut butter first. A friend of mine explained that the farmers rotate cotton & peanut crops. Cotton apparently needs lots of chemicals which get into the ground and then are later absorbed into the peanuts. So, if you pill your pooch using peanut butter consider getting her some organic stuff.
    I know I sound like a tree hugger but I'm really just a computer geek that likes to do research, and a dog lover who likes it when dogs & their owners are happy."

    Spirit

    Another woman from the canine cognitive dysfunction group on yahoo wrote

    "I took Spirit to see Dr. Sisson, the head neurologist at Angell Memorial in Boston. He is wonderful and very knowledgeable. Of course, as I suspected, he diagnosed Spirit with Canine Cognitive Dysfunction. He explained that these dogs are primarily happy, that the moaning that they do is usually because they need something but they are not in pain and it does not bother them.

    Dr. Sisson explained that the reason people put these dogs down is because the caregiver is unable to care for them but not because the dog is in any discomfort. This made me feel way way better! He also explained that eventually the brain can atrophy to the point where the dog is unable to breathe and then dies. However, he said that in his years as a neurologist he has never seen that happen.

    He prescribed two medications for Spirit, Anipryl and Acepromazine. The latter helps Spirit sleep through the night. It is such a relief because after a week I can see a difference. Just the sleep piece alone helps a great deal because I no longer feel as if I am a walking zombie and am able to care for him better.

    I also added Zypan from Standard Process and I could see a difference within a week."

    "
    Some also use alpha lipoic acid and r-lipoic acid. powerful antioxidants to help slow down canine cognitive dysfunction. There is a dog food that is rich in antioxidants for CDS but I am assuming if you supplement with your own antioxidants you don't have to worry if your dog likes the food or not. I know my dog Hammy has become very picky and at least if I pill him, I know he is getting his antioxidants.

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    They sell powerful antioxidants, especially for animals.
    some holistic suggestions for CDS
    Some people have used the supplement Neuro PS, Phosphatidylserine to help with the cognitive functioning. Melatonin, also an antioxidant with many great properties and which can go beyond the brain barrier, can be used to help your companion sleep if insomnia is one of the symptoms....Proneurozone..These are just suggestions. It is always wise to discuss whatever you give your companion with your vet!

    the generic version for Anipryl -SELEGILINE HYDROCHLORIDE SELEGILINE-

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    Indications: Formulated for veterinary use to remove organic stains and odors associated with pets, such as those caused by urine, feces, vomit, blood, and food, etc. Recommended for cleaning stains associated with: Puppy and kitten training, sick or debilitated animals, cat litter box aversion, and elimination behavior problems.
    Use on carpets, floors, furniture, clothing, auto interiors, litter boxes, cages, pet living and sleeping areas
    Ann Intern Med. 2003 Sep 2;139(5 Pt 2):441-4. : Gene-diet interactions in brain aging and neurodegenerative disorders.
    Mattson MP.
    Laboratory of Neurosciences, National Institute on Aging, Gerontology Research Center 4F01, 5600 Nathan Shock Drive, Baltimore, MD 21224, USA.
    mattsonm@grc.nia.nih.gov

    While there are many examples of people who live for 100 years or more with little evidence of a decline in brain function, many others are not so fortunate and experience a neurodegenerative disorder, such as Alzheimer disease or Parkinson disease. Although an increasing number of genetic factors that may affect the risk for neurodegenerative disorders are being identified, emerging findings suggest that dietary factors play major roles in determining whether the brain ages successfully or experiences a neurodegenerative disorder. Dietary factors may interact with disease-causing or predisposing genes in molecular cascades that either promote or prevent the degeneration of neurons. Epidemiologic findings suggest that high-calorie diets and folic acid deficiency increase the risk for Alzheimer disease and Parkinson disease; studies of animal models of these disorders have shown that dietary restriction (reduced calorie intake or intermittent fasting) and dietary supplementation with folic acid can reduce neuronal damage and improve behavioral outcome. Animal studies have shown that the beneficial effects of dietary restriction on the brain result in part from increased production of neurotrophic factors and cytoprotective protein chaperones in neurons. By keeping homocysteine levels low, folic acid can protect cerebral vessels and prevent the accumulation of DNA damage in neurons caused by oxidative stress and facilitated by homocysteine. Although additional studies are required in humans, the emerging data suggest that high-calorie diets and elevated homocysteine levels may render the brain vulnerable to age-related neurodegenerative disorders, particularly in persons with a genetic predisposition to such disorders.

    "Canine cognitive disorder. A major concern among owners is the cost of daily medication. There are other more natural alternatives, including herbal preparations (gingko, lycopodium, salvia), thyroid supplement (when hypothyroidism is the cause) and a product called Cholodin. In the author's practice, Cholodin is successfully combined with several whole-food supplements (RNA, Senaplex, Inositol; available from Standard Process.) Cholodin and these other supplements contain a number of nutritional compounds, including choline, phosphatidylcholine, methionine, inositol and various B vitamins. Choline provides methyl groups used by the body in a number of biological reactions and acts as a precursor of acetylcholine. Phosphatidylcholine (lecithin) is part of the plasma membrane of mammalian cells and also provides additional choline for acetylcholine synthesis. Methionine and inositol also are involved in neurotransmitter metabolism. This therapy has proven extremely effective in most dogs, without the expense or potential side effects of drug therapy. Therapy is given for 2 months to assess efficacy, although results may occur more quickly. Pets with hypothyroidism are also supplemented with thyroid medication. If dogs fail to improve on this regimen, Anipryl can be used once the diagnosis is reconfirmed. For a more holistic approach, this regimen works quite well." Shawn Messonnier, DVM - Veterinary Product News, October 1999
    entirelypets.com sells cholodin

    Canine Brain Aging: From Diagnosis to Management
    Neurobiol Aging. 2002 Sep-Oct;23(5):809-18. : Brain aging in the canine: a diet enriched in antioxidants reduces cognitive dysfunction.
    Cotman CW, Head E, Muggenburg BA, Zicker S, Milgram NW.
    Institute for Brain Aging and Dementia, University of California, 1226 Gillespie Neuroscience Research Facility, Irvine, CA 92697-4540, USA.
    cwcotman@uci.edu

    Animal models that simulate various aspects of human brain aging are an essential step in the development of interventions to manage cognitive dysfunction in the elderly. Over the past several years we have been studying cognition and neuropathology in the aged-canine (dog). Like humans, canines naturally accumulate deposits of beta-amyloid (Abeta) in the brain with age. Further, canines and humans share the same Abeta sequence and also first show deposits of the longer Abeta1-42 species followed by the deposition of Abeta1-40. Aged canines like humans also show increased oxidative damage. As a function of age, canines show impaired learning and memory on tasks similar to those used in aged primates and humans. The extent of Abeta deposition correlates with the severity of cognitive dysfunction in canines. To test the hypothesis that a cascade of mechanisms centered on oxidative damage and Abeta results in cognitive dysfunction we have evaluated the cognitive effects of an antioxidant diet in aged canines. The diet resulted in a significant improvement in the ability of aged but not young animals to acquire progressively more difficult learning tasks (e.g. oddity discrimination learning). The canine represent a higher animal model to study the earliest declines in the cognitive continuum that includes age associated memory impairments (AAMI) and mild cognitive impairment (MCI) observed in human aging. Thus, studies in the canine model suggest that oxidative damage impairs cognitive function and that antioxidant treatment can result in significant improvements, supporting the need for further human studies. Copyright 2002 Elsevier Science Inc.
    Prevalence of behavioral changes associated with age-related cognitive impairment in dogs
    Jacqueline C. Neilson, DVM, DACVB; Benjamin L. Hart, DVM, PhD, DACVB; Kelly D. Cliff, DVM; William W. Ruehl, DVM, PhD, DACVP, J Am Vet Med Assoc 2001;218:1787–1791

    Abstract
    Objective—To determine the prevalence of age-related behavioral changes, namely impairment, in a randomly chosen population of dogs.
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    Design—Age-stratified cohort study.
    Animals—97 spayed female and 83 castrated male dogs that were 11 to 16 years old.
    Procedure—Data on possible impairment in 4 behavioral categories (ie, orientation in the home and yard, social interaction, house training, and sleep-wake cycle) linked to cognitive dysfunction were obtained from dog owners, using a structured telephone interview. Hospital records of dogs had been screened to exclude dogs with dysfunction in organ systems that may cause behavioral changes. Dogs with behavioral impairment were those with = 2 signs of dysfunction within a category. Dogs with impairment in 1 category were considered mildly impaired and those with impairment in = 2 categories were considered severely impaired.
    Results—Age by sex interactions for dogs with impairment in any category were not significant, and, therefore, data on castrated males and spayed females were pooled for analyses across ages. The prevalence of age-related progressive impairment was significant in all categories. The percentage of 11- to 12-year-old dogs with impairment in = 1 category was 28% (22/80), of which 10% (8/80) had impairment in = 2 behavioral categories. Of 15- to 16-year-old dogs, 68% (23/34) had impairment in = 1 category, of which 35% (12/34) had impairments in = 2 categories. There were no significant effects of body weight on the prevalence of signs of dysfunction in the behavioral categories.
    Conclusions and Clinical Relevance—Data collected provide estimates of the prevalence of various degrees of age-related behavioral changes associated with cognitive dysfunction in dogs. Age-related behavioral changes may be useful indicators for medical intervention for dogs with signs of cognitive impairment. (J Am Vet Med Assoc 2001;218:1787–1791)
    --------------------------------------------------------------------------------
    From the Animal Behavior Clinic, 809 SE Powell, Portland, OR 97202 (Neilson); and the Behavior Service, Veterinary Medical Teaching Hospital (Hart), and the Department of Anatomy, Physiology, and Cell Biology (Cliff), School of Veterinary Medicine, University of California, Davis, CA 95616; and 13868 Skyline Blvd, Woodside, CA 94062 (Ruehl). Supported in part by Friskies PetCare Residency Program in Clinical Animal Behavior at the University of California, Davis, the UC Davis Center for Companion Animal Health, and Deprenyl Animal Health, Overland Park, Kan. The authors thank Dr. David Bruyette for technical assistance and Dr. Neil Willits for statistical assistance. Address correspondence to Dr. Hart.BEHAVIOR PROBLEMS IN THE GERIATRIC DOG AND CAT
    Gary Landsberg, BSc, DVM, Diplomate ACVB Doncaster Animal Clinic, Thornhill, Ontario

    Aging, the Brain, and cognitive dysfunction-great descriptions
    No To Shinkei. 2002 Dec;54(12):1041-8. : [Long-term treatment of Parkinson's disease patients with selegiline hydrochloride (FPF 1100): outcome of 5-year treatment]
    [Article in Japanese]
    Kondo T, Takubo H, Yokochi F, Okuma Y, Mizuno Y.
    Department of Neurology, Juntendo University School of Medicine, Japan.

    We herein report on the outcome of 5 year-treatment of Parkinson's disease patients with selegiline hydrochloride. The subjects participated in this study were 10 patients whose treatment had been maintained consecutively by administration of this agent even after completion of the Phase II trial (all cases under adjunct therapy with L-DOPA/DCI). The daily dose of selegiline hydrochloride was 6.6 +/- 2.5 mg in average at the end and/or termination of the study. As for L-DOPA, its daily dose decreased from 410 +/- 160 mg to 365 +/- 133 mg at the 6th month, but the dose reduction level after 9 months was not determinable due to an increase in dropouts. Regarding alteration in the scores for individual symptoms, improvement in wearing-off symptom was pronounced during the treatment period of 3 to 51 months. The Global Improvement Rate and Usefulness Rate remained stable during the period of 18 to 30 months treatment although these rates declined after 36 months probably because of exacerbation in disease conditions. This study may assure tolerability of selegiline hydrochloride in a long-term treatment of Parkinson's disease patients.
    : Prescrire Int. 2002 Aug;11(60):108-11. : Selegiline: a second look. Six years later: too risky in Parkinson's disease.
    [No authors listed]

    1) The reference treatment for Parkinson's disease is levodopa plus a peripheral dopadecarboxylase inhibitor (benserazide or carbidopa). (2) In 1996, selegiline, a type B MAOI marketed in France since 1988, saw its indications extended to cover single-agent therapy of early-stage Parkinson's disease, and in combination with levodopa, before onset of complications of levodopa therapy. The initial clinical file failed to show that selegiline had any benefit in these indications. (3) Now, in 2002, new data from trials involving hundreds of untreated patients show that selegiline postpones the need for levodopa therapy for a few months but fails to substantially alter the progression of Parkinson's disease. (4) A clinical trial and a retrospective epidemiological study of patients with advanced Parkinson's disease showed excess mortality on selegiline. (5) The side effects of selegiline are similar to those of other antiparkinsonian drugs and amphetamine. Notable side effects include cardiovascular problems (postural hypotension, atrial fibrillation and arterial hypertension). (6) Selegiline can cause a serotoninergic syndrome and arterial hypertension, so must not be combined with pethidine, tramadol, bupropion, sumatriptan, zolmitriptan or naratriptan. Concurrent treatment with serotonin reuptake inhibitor antidepressants should also be avoided. (7) Given the only moderate effects of selegiline in Parkinson's disease, and the possibility of a slight increase in mortality, there is no justification for prescribing this medication in patients with Parkinson's disease. (8) Whatever the stage of Parkinson's disease, there is no justification for starting patients on selegiline. Patients who are already taking selegiline should only continue to take it if they feel a clear benefit and are free from risk factors for early mortality, especially cardiovascular disease.
    J Neurosci Res. 2002 Feb 1;67(3):285-9. : Neuroprotective actions of selegiline.
    Ebadi M, Sharma S, Shavali S, El Refaey H.
    Department of Pharmacology, Physiology, and Therapeutics, University of North Dakota School of Medicine and Health Sciences, Grand Forks, North Dakota 58203, USA.
    mebadi@medicine.nodak.edu

    Selegiline, a selective inhibitor of monoamine oxidase-B (MAO-B), was one of the first adjunct therapies in clinical neurology. A retrospective analysis of data from patients with Parkinson's disease found a significant increase in survival in those treated with selegiline plus L-dopa compared with L-dopa alone. The mechanism of action of selegiline is complex and cannot be explained solely by its MAO-B inhibitory action. Pretreatment with selegiline can protect neurons against a variety of neurotoxins, such as 1-methyl-4-phenyl-1,2,3,6 tetrahydropyridine (MPTP), 6-hydroxydopamine, N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP-4), methyl-beta-acetoxyethyl-2-chloroethylamine (AF64A), and 5,6-dihydroxyserotonin, which damage dopaminergic, adrenergic, cholinergic, and sertoninergic neurons, respectively. Selegiline produces an amphetamine-like effect, enhances the release of dopamine, and blocks the reuptake of dopamine. It stimulates gene expression of L-aromatic amino acid decarboxylase, increases striatal phenylethylamine levels, and activates dopamine receptors. Selegiline reduces the production of oxidative radicals, up-regulates superoxide dismutase and catalase, and suppresses nonenzymatic and iron-catalyzed autooxidation of dopamine. Selegiline compensates for loss of target-derived trophic support, delays apoptosis in serum-deprived cells, and blocks apoptosis-related fall in the mitochondrial membrane potential. Most of the aforementioned properties occur independently of selegiline's efficacy to inhibit MAO-B. Copyright 2002 Wiley-Liss, Inc.
    Predicting behavioral changes associated with age-related cognitive impairment in dogs
    Melissa J. Bain, DVM; Benjamin L. Hart, DVM, PhD, DACVB; Kelly D. Cliff, DVM; William W. Ruehl, DVM, PhD, DACVP *

    Abstract
    Objective—To monitor the progression of age-related behavioral changes in dogs during a period of 6 to 18 months and to determine whether signs of dysfunction in any of 4 behavioral categories can be used to predict further impairment.

    Design—Age-stratified cohort study.

    Animals—63 spayed female and 47 castrated male dogs 11 to 14 years of age.

    Procedure—Data were collected from randomly selected dog owners who were interviewed by telephone twice at a 12- to 18-month interval; data were included if the dog had lived = 6 months between interviews. The interview focused on signs of impairment in the following behavioral categories: orientation in the home and yard, social interactions with human family members, house training, and the sleep-wake cycle. Dogs were determined to have impairment in 0 behavioral categories (on the basis of = 1 sign for each category), impairment in 1 category (= 2 signs of dysfunction in that category), or impairment in = 2 categories.

    Results—Between interviews, 22% (16/73) of dogs that did not have impairment in a category at the time of the first interview developed impairment in that category by the time of the second interview. Forty-eight percent (13/27) of dogs that had impairment in 1 category at the time of the first interview developed impairment in = 2 categories by the time of the second interview and were significantly more likely to develop impairment in = 2 categories, compared with dogs that initially had impairment in 0 categories. Dogs with 1 sign of dysfunction in orientation were significantly more likely to develop impairment in that category, compared with dogs that had 0 signs of dysfunction in orientation.
    Conclusions and Clinical Relevance—Age-related behavioral changes in dogs are progressive. Clinicians should consider trying to predict which dogs are most likely to become progressively impaired during the subsequent 6 to 18 months. (J Am Vet Med Assoc 2001;218:1792–1795)


    From the Behavior Service, Veterinary Medical Teaching Hospital (Bain, Hart), and the Department of Anatomy, Physiology, and Cell Biology (Cliff), School of Veterinary Medicine, University of California, Davis, CA 95616; and 13868 Skyline Blvd, Woodside, CA 94062 (Ruehl). Supported in part by Friskies PetCare Residency Program in Clinical Animal Behavior at the University of California, Davis, the UC Davis Center for Companion Animal Health, and Deprenyl Animal Health, Overland Park, Kan. The authors thank Dr. David Bruyette for technical assistance and Dr. Neil Willits for statistical assistance. Address correspondence to Dr. Hart.

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    Can Immunization with Fibrillar Ab Prevent Alzheimer's Disease
    Immunization with Fibrillar Ab may one day effectively reduce or eliminate the development of abnormal brain function in the elderly.
    Fibrillar Ab , or beta-amyloid, is a protein which forms thick deposits, or plaques, in the brains of people with Alzheimer's disease, a disease where memory skills gradually deteriorate with age. Small amounts of this protein can be found in the cerebral cortex of normal elderly people, so we don't know if fibrillar Ab causes Alzheimer's or is a byproduct of the disease.
    If immunization with small amounts of fibrillar Ab prevents the formation of filaments in the brain, LRRI scientists will know whether those deposits cause Alzheimer's and we will be one step closer to finding a cure for that debilitating disease.
    Over the past 10 years, studies have demonstrated that aged canines show a decline in memory and learning and a corresponding increase in fibrillar Ab . In addition, recent data support an association specifically between cognitive test scores and the location and extent of beta-amyloid protein in the brain.
    Dr. Edward Barrett in collaboration with colleagues from UCI recently received a $1,167,010 grant from the National Institutes of Health to study "Ab Immunization in a Canine Model of Aging."
    The evidence suggests that b-amyloid (Ab ) deposits may not form in a transgenic mouse model that were immunized fibrillar Ab . Further, memory decline appears to be reduced in immunized mice.
    We propose to replicate and extend these studies in mice to a higher mammalian model, the aged canine (dog).
    The questions we hope to answer specifically are:
    (1) will immunization with fibrillar Ab reduce the development of cognitive dysfunction in aged canines;
    (2) will immunization reduce long-lived species of Ab , which are more highly aggregated and insoluble, typical of both aged human and canine brain;
    (3) is the reduction of Ab in the brain through immunization possible in immunologically intact animal models and;
    (4) are secondary pathologies related to A also reduced? (e.g. inflammation, neuritic dystrophy, gliosis, oxidative damage)
    All dogs will undergo extensive baseline testing to evaluate learning (visual discrimination) and memory (object recognition and spatial) ability.
    After the start of intervention, learning will be evaluated at regular intervals using new visual discrimination tasks. Memory will be re-evaluated using the same object recognition and spatial memory tasks that are designed for repeated testing. At the conclusion of the study, evidence of an autoimmune or inflammatory response will be determined by necropsy.
    The proposed studies provide a test of the theory that Ab causes cognitive dysfunction. Overall, this project should provide unique insight into the efficacy of immunization with fibrillar Ab with direct implications for the design of human clinical trials.
    Neurobiol Aging. 2002 Sep-Oct;23(5):737-45. : Dietary enrichment counteracts age-associated cognitive dysfunction in canines.
    Milgram NW, Zicker SC, Head E, Muggenburg BA, Murphey H, Ikeda-Douglas CJ, Cotman CW.
    Life Science Division, University of Toronto at Scarborough, 1265 Military Trail, Scarborough, Ont, Canada M1C 1A4.
    milgram@psych.utoronto.ca

    Advanced age is accompanied by cognitive decline indicative of central nervous system dysfunction. One possibly critical causal factor is oxidative stress. Accordingly, we studied the effects of dietary antioxidants and age in a canine model of aging that parallels the key features of cognitive decline and neuropathology in humans. Old and young animals were placed on either a standard control food, or a food enriched with a broad spectrum of antioxidants and mitochondrial enzymatic cofactors. After 6 months of treatment, the animals were tested on four increasingly difficult oddity discrimination learning problems. The old animals learned more slowly than the young, making significantly more errors. However, this age-associated decline was reduced in the animals fed the enriched food, particularly on the more difficult tasks. These results indicate that maintenance on foods fortified with complex mixtures of antioxidants can partially counteract the deleterious effects of aging on cognition. Copyright 2002 Elsevier Science Inc.
    J Nutr. 2002 Jun;132(6 Suppl 2):1579S-82S. : Aspects of neurodegeneration in the canine brain.
    Dimakopoulos AC, Mayer RJ.
    School of Biomedical Sciences, University of Nottingham, Medical School, Queens Medical Centre, Nottingham, NG7 ZUH UK.
    The process of neurodegeneration displays some common morphological characteristics, most of which are jointly observed in the brains of most mammalian species. In the canine brain, neurodegeneration is frequently typified by an extensive beta-amyloid (A beta) deposition (mainly of the C-terminal A beta1-42 form) within the neurones and at the synaptic regions, in the early stages of the process. These deposits subsequently appear to give rise to the formation of senile plaques of the diffuse (non-beta-sheet) subtype, which tend to develop spontaneously but rarely proceed to form neuritic plaques. Additional features accompanying neurodegeneration include accumulations of the "aging pigment," lipofuscin, intraneuronal changes in the cytoskeleton, vascular changes in the cerebrum, cortical cerebral atrophy, enlargement of the ventricles and increased concentration of oxidative stress markers, many of which are perceived as cardinal features of extensive dysfunction in the protein turnover network. The involvement of ubiquitin is discrete but consistent in many of these molecular structures and seems to account for some critical aspects of the associated neuropathology. Irrespective of these, though, the degenerated canine brain seems to be devoid of neurofibrillary tangle formation, a manifestation commonly observed in the brain of both aged (cognitively normal) and Alzheimer-affected human subjects. The fact that canines exhibit clear symptoms of an age-related cognitive decline pertains to the concept of A beta playing a central role in age-related cognitive dysfunction and neurodegeneration.
    Vet Pathol. 1999 May;36(3):202-11. : Age-related changes in the brain of the dog.
    Borras D, Ferrer I, Pumarola M
    . Department of Pathology and Animal Science, Faculty of Veterinary Medicine, Universitat Autonoma de Barcelona, Bellaterra, Spain.
    Daniel.Borras@cc.uab.es

    Although many age-related changes have been described in the nervous system of different species, few authors have specifically studied the topic. Knowledge of such changes is essential to veterinary pathologists, who must distinguish the lesions of specific pathologic processes from those arising as a result of normal aging. The brains of 20 old dogs, ranging in age from 8 to 18 years, were compared with those of 10 young dogs using routine staining techniques (hematoxilin and eosin, periodic acid-Schiff), special staining techniques (periodic acid-methenamine silver stain), and immunohistochemical techniques to detect glial fibrillary acid protein, neurofilaments, ubiquitin, and beta-amyloid. Changes affected meninges and choroid plexuses, meningeal and parenchymal vessels, neurons, and glial cells. Of special interest was the presence of polyglucosan bodies, cerebrovascular amyloid deposition, senile plaques, and ubiquitinated bodies. Some of the age-related changes found, particularly lipofuscin, polyglucosan bodies, and beta-amyloid protein deposition, may play a role in the pathogenesis of the canine cognitive dysfunction syndrome. The dog could be used as a natural animal model for the study of normal aging and human neurodegenerative diseases
    Neurobiol Learn Mem. 1996 Jul;66(1):11-23. : Beta-amyloid accumulation correlates with cognitive dysfunction in the aged canine.
    Cummings BJ, Head E, Afagh AJ, Milgram NW, Cotman CW.
    Institute for Brain Aging and Dementia, University of California at Irvine, Irvine, California, 92717-4550, USA.

    It is well known that beta-amyloid accumulates abnormally in Alzheimer's disease; however, beta-amyloid's relationship to cognitive dysfunction has not been clearly established and is often confounded by the presence of neurofibrillary tangles. We used canines to investigate the relationship between beta-amyloid accumulation and cognitive function in an animal model of aging lacking neurofibrillary tangles. The performance of 20 canines (11 purebred beagles and 9 mongrels) on a battery of six cognitive tasks was measured. These tasks included Reward Approach and Object Approach learning, as well as Discrimination, Reversal, Object Recognition, and Spatial learning and memory. Aged canines were impaired on some tasks but not others. beta-Amyloid-immunopositive plaques were found in many of the older animals. Plaques were all of the diffuse subtype and many contained intact neurons detected with double-labeling for neurofilaments. No neurofibrillary tangles were detected. beta-Amyloid was also associated with the processes of many neurons and with blood vessels. Using computerized image analysis, we quantified the area occupied by beta-amyloid in entorhinal cortex, frontal cortex, and cerebellum. Controlling for age-related increases in beta-amyloid, we observed that increased beta-amyloid deposition is strongly associated with deficits on Discrimination learning (r = .80), Reversal learning (r = .65), and Spatial learning (r = .54) but not the other tasks. There were a few differences between breeds which are discussed in the text. Overall, these data suggest that beta-amyloid deposition may be a contributing factor to age-related cognitive dysfunction prior to the onset of neurofibrillary tangle formation.
    J Am Vet Med Assoc. 2001 Jul 1;219(1):51-6. : Effect of gonadectomy on subsequent development of age-related cognitive impairment in dogs.
    Hart BL.
    Behavior Service, Veterinary Medical Teaching Hospital, School of Veterinary Medicine, University of California, Davis, CA 95616, USA.

    OBJECTIVE: To determine whether gonadectomy predisposes dogs to development of age-related behavioral changes linked to cognitive impairment. DESIGN: Cohort study. ANIMALS: 29 sexually intact male dogs, 63 spayed female dogs, and 47 castrated male dogs 11 to 14 years old. PROCEDURE: Information on possible impairments in 4 behavioral categories linked to cognitive impairment (orientation in the home and yard, social interactions, house training, and sleep-wake cycle) was obtained from owners of the dogs by use of a structured telephone interview format. A second interview was performed 12 to 18 months after the initial interview, and differences in responses were evaluated. RESULTS: Sexually intact male dogs were significantly less likely than neutered dogs to progress from mild impairment (i.e., impairment in 1 category) to severe impairment (i.e., impairment in > or = 2 categories) during the time between the first and second interviews. This difference was not attributable to differences in ages of the dogs, duration of follow-up, or the owners' perceptions of the dogs' overall health. CONCLUSIONS AND CLINICAL RELEVANCE: Results suggest that the presence of circulating testosterone in aging sexually intact male dogs may slow the progression of cognitive impairment, at least among dogs that already have signs of mild impairment. Estrogens would be expected to have a similar protective role in sexually intact female dogs; unfortunately, too few sexually intact female dogs were available for inclusion in the study to test this hypothesis. There may be a need to evaluate possible methods for counteracting the effects of loss of sex hormones in gonadectomized dogs.
    J Neurochem. 2002 Jul;82(2):375-81. : Oxidative damage increases with age in a canine model of human brain aging.
    Head E, Liu J, Hagen TM, Muggenburg BA, Milgram NW, Ames BN, Cotman CW.
    Institute for Brain Aging and Dementia, University of California, Irvine, California 92697-4540, USA.
    ehead@uci.edu

    We assayed levels of lipid peroxidation, protein carbonyl formation, glutamine synthetase (GS) activity and both oxidized and reduced glutathione to study the link between oxidative damage, aging and beta-amyloid (Abeta) in the canine brain. The aged canine brain, a model of human brain aging, naturally develops extensive diffuse deposits of human-type Abeta. Abeta was measured in immunostained prefrontal cortex from 19 beagle dogs (4-15 years). Increased malondialdehyde (MDA), which indicates increased lipid peroxidation, was observed in the prefrontal cortex and serum but not in cerebrospinal fluid (CSF). Oxidative damage to proteins (carbonyl formation) also increased in brain. An age-dependent decline in GS activity, an enzyme vulnerable to oxidative damage, and in the level of glutathione (GSH) was observed in the prefrontal cortex. MDA level in serum correlated with MDA accumulation in the prefrontal cortex. Although 11/19 animals exhibited Abeta, the extent of deposition did not correlate with any of the oxidative damage measures, suggesting that each form of neuropathology accumulates in parallel with age. This evidence of widespread oxidative damage and Abeta deposition is further justification for using the canine model for studying human brain aging and neurodegenerative diseases.
    Neurobiol Dis. 2002 Feb;9(1):1-10. : Insights into Abeta and presenilin from a canine model of human brain aging.
    Head E, Torp R
    . Institute for Brain Aging & Dementia, University of California, 1226 Gillespie Neuroscience Research Facility, Irvine, California 92697-4540, USA.
    ehead@uci.edu
    In this review, we describe insights into beta-amyloid (Abeta) production using aged dogs as a model of human brain aging. The advantage of using dogs is that they naturally accumulate Abeta neuropathology with age. In parallel, dogs also develop age-associated learning and memory impairments. Thus, dogs can complement existing transgenic and nonhuman primate models typically used in aging studies. Dogs can live up to 18-19 years of age and companion dogs share the same environment as humans. Morphological brain changes as a function of age are clearly visible in vivo using magnetic image resonance scans. At the light microscopic level, dogs accumulate diffuse plaques with a distribution similar to that observed in human brain. Confocal studies suggest that Abeta accumulates on neuronal membranes in a segregated pattern. This pattern has been confirmed at the ultrastructural level using electron microscopy and provides insight into the deposition of Abeta into the extracellular space, possibly prior to overt plaque formation. Further, double immunogold labeling studies demonstrate that Abeta associated with the plasma membrane is colocalized with presenilin. These in vivo observations suggest a common site for both Abeta and presenilin supporting the hypothesis that the latter is involved with APP processing.
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    Prog Neuropsychopharmacol Biol Psychiatry. 2000 Jul;24(5):787-99. : DNA damage and apoptosis in the aged canine brain: relationship to Abeta deposition in the absence of neuritic pathology.
    Anderson AJ, Ruehl WW, Fleischmann LK, Stenstrom K, Entriken TL, Cummings BJ.
    Institute for Brain Aging and Dementia, University of California, Irvine 92696-4540, USA.

    1. In addition to beta-amyloid (Abeta) deposition and cytoskeletal neuropathology, both the Alzheimer's disease (AD) and Down's syndrome (DS) human brain exhibit marked evidence of DNA damage, however, it is difficult to separate events that occur in conjunction with neurofibrillary pathology versus Abeta pathology in these systems. 2. In contrast, the aged canine brain exhibits the accumulation of Abeta into diffuse deposits similar to those found in early AD and DS in the absence of neurofibrillary pathology. Furthermore, Abeta deposition in canine brain is correlated with cognitive deficits. 3. In order to test the hypothesis that TUNEL labeling for DNA damage in AD is not simply a consequence of agonal artifacts, postmortem artifacts, or neurofibrillary pathology, and may be directly related to Abeta deposition, we examined Abeta immunoreactivity, PHF-1 immunoreactivity, and TUNEL labeling in this animal model. 4. These experiments reveal a relationship between the amount of DNA damage detected by TUNEL labeling and levels of Abeta deposition. Further, in animals with no TUNEL labeling, we detected no Abeta immunoreactivity. 5. These data support the hypothesis that TUNEL labeling in AD ans DS is not a consequence of agonal artifact, postmortem artifact, or tau pathology, and may be directly related to Abeta deposition and perhaps AD pathogenesis
    J Am Vet Med Assoc. 2002 May 1;220(9):1315-20. : Effects of diet restriction on life span and age-related changes in dogs.
    Kealy RD, Lawler DE, Ballam JM, Mantz SL, Biery DN, Greeley EH, Lust G, Segre M, Smith GK, Stowe HD.
    Pet Nutrition Research Department, Nestle Purina Pet Care Co, St Louis, MO 63164, USA.

    OBJECTIVE: To evaluate the effects of 25% diet restriction on life span of dogs and on markers of aging. DESIGN: Paired feeding study. ANIMALS: 48 Labrador Retrievers. PROCEDURES: Dogs were paired, and 1 dog in each pair was fed 25% less food than its pair-mate from 8 weeks of age until death. Serum biochemical analyses were performed, body condition was scored, and body composition was measured annually until 12 years of age. Age at onset of chronic disease and median (age when 50% of the dogs were deceased) and maximum (age when 90% of the dogs were deceased) life spans were evaluated. RESULTS: Compared with control dogs, food-restricted dogs weighed less and had lower body fat content and lower serum triglycerides, triiodothyronine, insulin, and glucose concentrations. Median life span was significantly longer for dogs in which food was restricted. The onset of clinical signs of chronic disease generally was delayed for food-restricted dogs. CONCLUSIONS AND CLINICAL RELEVANCE: Results suggest that 25% restriction in food intake increased median life span and delayed the onset of signs of chronic disease in these dogs.
    J Nutr. 2003 Sep;133(9):2887-92. : Improved glucose tolerance with lifetime diet restriction favorably affects disease and survival in dogs.
    Larson BT, Lawler DF, Spitznagel EL Jr, Kealy RD.
    Nestle Purina PetCare Research, St. Louis, MO 63164 and. Department of Mathematics, Washington University, St. Louis, MO 63130.

    Labrador retrievers (42 of original 48) were used to assess the effects of lifetime diet restriction on glucose tolerance at ages 9-12 y. Restricted-fed (RF) dogs were fed 75% of the same diet consumed by control-fed (CF) pair-mates. An intravenous glucose tolerance test was done annually (maximal stimulation, nonsteady-state). Diet treatment, age, and interactions were fixed effects. Statistical procedures used included mixed-model, repeated-measures ANOVA; least-squares means; Tukey's multiple comparison; paired t tests; and Spearman rank correlations. Glucose k-value and half-life, and insulin sensitivity (total, and 9, 10, 11 y, and per lean mass) were higher (P < 0.05) in RF than in CF dogs. Late-phase insulin release [area under the curve (AUC) 30-120 min] was less (P < 0.05) in RF than in CR dogs. Early-phase insulin release (AUC 0-5 min), y 12 insulin sensitivity and insulinogenic index did not differ between RF and CF dogs. Insulin peak, Delta and total AUC increased (P < 0.05) with age, whereas the glucose k-value and glucose half-life were not affected by age. Insulin sensitivity was negatively, and insulin AUC 30-120 min, peak and Delta glucose were positively correlated with body weight, body condition score, fat mass, percentage of fat and abdominal fat/total tissue. Higher insulinogenic indices tended (P = 0.053) to be associated with greater median survival and dogs with higher insulin sensitivity were at lower (P < 0.05) risk of dying or receiving chronic disease treatment. Time to first osteoarthritis treatment or death was greater with lower basal glucose and higher insulin sensitivity (P < 0.05), but diet restriction explained most of this relationship's variation. Glucose disposal efficiency and insulin response were associated with increased quality and length of life in diet-restricted dogs.
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