Abstract
The present review focuses on the utility of a canine model in evaluating nutritional interventions for age-related cognitive dysfunction. Aged dogs demonstrate progressive cognitive decline with concurrent amyloid-beta pathology that parallels the pathology observed in aging humans. Dogs, therefore, provide a natural model of human pathological aging. We have and are in the process of evaluating several nutritional-based interventions aimed at preventing cognitive decline and brain aging. In a three-year longitudinal study, we examined the effects of a diet enriched with antioxidants and mitochondrial cofactors on several measures of cognition and brain aging. Compared to controls, aged dogs on the enriched diet demonstrated both short- and long-term cognitive benefits, as well decreased deposition of amyloid-beta protein. The diet also reduced behavioral signs associated with canine Cognitive Dysfunction Syndrome when assessed in veterinary clinical trials. We also have preliminary evidence suggesting a beneficial effect of a proprietary blend of docosahexaenoic acid and phospholipids on both cognitive and physiological measures. Collectively, our data indicate (1) that the dog, either in the laboratory or in the clinic, provides an important tool for assessing nutritional interventions and (2) that combination interventions aimed at several mechanisms of pathological aging may prove more effective than single nutritive components in human trials.
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Abbreviations
- Aβ:
-
amyloid-beta
- CDS:
-
cognitive dysfunction syndrome
- DHA:
-
docosahexaenoic acid
- DNMP:
-
delayed-non-matching-to-position
References
Adams B, Chan A, Callahan H and Milgram NW (2000a) The canine as a model of human cognitive aging: recent developments. Prog Neuro-Psychopharmacol Biol Psychiatry 24(5): 675–692
Adams B, Chan A, Callahan H, Siwak C, Tapp D and Ikeda-Douglas C et al. (2000b) Use of a delayed non-matching to position task to model age-dependent cognitive decline in the dog. Behav Brain Res 108(1): 47–56
Amaducci L (1988) Phosphatidylserine in the treatment of Alzheimer’s disease: results of a multicenter study. Psychopharmacol Bull 24(1): 130–134
Ames BN, Shigenaga MK and Hagen TM (1993) Oxidants, antioxidants, and the degenerative diseases of aging. Proc Nat Acad Sci USA 90(17): 7915–7922
Araujo JA (2004) Age-dependent learning and memory decline in dogs: assessment and effectiveness of various interventions. In: Conference Proceedings of the American Veterinary Medical Association, Schaumberg, IL
Araujo JA, Studzinski CM, Siwak CT, Head E and Milgram NW (2004a) Cognitive function and aging in beagle dogs. In: Conference Proceedings of the American College of Veterinary Internal Medicine (http://www.vin.com/Members/Proceedings/)
Araujo JA, Studzinski CM, Head E, Cotman CW and Milgram NW (2004b) Behavioral enrichment and supplementation with antioxidants and mitochondrial cofactors reduce the development of age-dependent cognitive dysfunction in the aged beagle dog. In: Conference Proceedings of the 95th AOCS Annual Meeting and Expo (http://www.aocs.org/archives/am2004/)
Bain MJ, Hart BL, Cliff KD and Ruehl WW (2001) Predicting behavioral changes associated with age-related cognitive impairment in dogs. J Am Vet Med Assoc 218(11): 1792–1795
Bartus RT (2000) On neurodegenerative diseases, models, and treatment strategies: lessons learned and lessons forgotten a generation following the cholinergic hypothesis. Exp Neurol 163(2): 495–529
Beal MF (1995) Aging, energy, and oxidative stress in neurodegenerative diseases. Ann Neurol 38(3): 357–366
Bickford PC, Gould T, Briederick L, Chadman K, Pollock A and Young D et al. (2000) Antioxidant-rich diets improve cerebellar physiology and motor learning in aged rats. Brain Res 866(1–2): 211–217
Borras D, Ferrer I and Pumarola M (1999) Age-related changes in the brain of the dog. Vet Pathol 36(3): 202–211
Braak H and Braak E (1997) Staging of Alzheimer-related cortical destruction. Int Psychogeriatr 9(Suppl 1): 257–261
Calon F, Lim GP, Yang F, Morihara T, Teter B and Ubeda O et al. (2004) Docosahexaenoic acid protects from dendritic pathology in an Alzheimer’s disease mouse model. Neuron 43(5): 633–645
Chan AD, Nippak PM, Murphey H, Ikeda-Douglas CJ, Muggenburg B and Head E et al. (2002) Visuospatial impairments in aged canines (Canis familiaris): the role of cognitive–behavioral flexibility. Behav Neurosci 116(3): 443–454
Clinicaltrials.gov (2004) Internet reference. Retrieved from http://www.clinicaltrials.gov/ct/show/NCT00090402?order=29 on 3 January 2005
Cogan DG (1979) Visuospatial dysgnosia. Am J Ophthalmol 88(3 Pt 1): 361–368
Conquer JA, Tierney MC, Zecevic J, Bettger WJ and Fisher RH (2000) Fatty acid analysis of blood plasma of patients with Alzheimer’s disease, other types of dementia, and cognitive impairment. Lipids 35(12): 1305–1312
Cotman CW, Head E, Muggenburg BA, Zicker S and Milgram NW (2002) Brain aging in the canine: a diet enriched in antioxidants reduces cognitive dysfunction. Neurobiol Aging 23(5): 809–818
Cummings BJ, Head E, Ruehl W, Milgram NW and Cotman CW (1996a) The canine as an animal model of human aging and dementia. Neurobiol Aging 17(2): 259–268
Cummings BJ, Head E, Afagh AJ, Milgram NW and Cotman CW (1996b) Beta-amyloid accumulation correlates with cognitive dysfunction in the aged canine. Neurobiol Learn Mem 66(1): 11–23
Cummings BJ, Satou T, Head E, Milgram NW, Cole GM and Savage MJ et al. (1996c) Diffuse plaques contain C-terminal A beta 42 and not A beta 40: evidence from cats and dogs. Neurobiol Aging 17(4): 653–659
Dahme E (1962) Pathologische befunde an den Hirngefäßen bei tieren: die veränderungen der Hirngefäßen beim alten hund. Acta Neuropathol 1(Suppl): 54–60
Dahme E (1967) On the problem of the primary amyloid in menix and cerebral cortex vessels in dogs. Dtsch Tierarztl Wochenschr 74: 134–138
Dahme E (1968) Aging changes in the brain of the animal. Bull Schweiz Akad Med Wiss 24: 133–143
Di Matteo V and Esposito E (2003) Biochemical and therapeutic effects of antioxidants in the treatment of Alzheimer’s disease, Parkinson’s disease, and amyotrophic lateral sclerosis. Curr Drug Targets-CNS Neurol Dis 2(2): 95–107
Engelhart MJ, Geerlings MI, Ruitenberg A, van Swieten JC, Hofman A and Witteman JC et al. (2002) Dietary intake of antioxidants and risk of Alzheimer disease. J Am Med Assoc 287(24): 3223–3229
Ferrer I, Pumarola M, Rivera R, Zujar MJ, Cruz-Sanchez F and Vidal A (1993) Primary central white matter degeneration in old dogs. Acta Neuropathol 86(2): 172–175
Flicker C, Bartus RT, Crook TH and Ferris SH (1984) Effects of aging and dementia upon recent visuospatial memory. Neurobiol Aging 5(4): 275–283
Gamoh S, Hashimoto M, Hossain S and Masumura S (2001) Chronic administration of docosahexaenoic acid improves the performance of radial arm maze task in aged rats. Clin Exp Pharmacol Physiol 28(4): 266–270
Gearing M, Tigges J, Mori H and Mirra SS (1996) A beta40 is a major form of beta-amyloid in nonhuman primates. Neurobiol Aging 17(6): 903–908
Grodstein F, Chen J and Willett WC (2003) High-dose antioxidant supplements and cognitive function in community-dwelling elderly women. Am J Clin Nutr 77(4): 975–984
Gunning-Dixon FM and Raz N (2003) Neuroanatomical correlates of selected executive functions in middle-aged and older adults: a prospective MRI study. Neuropsychologia 41(14): 1929–1941
Halliwell B (1992) Reactive oxygen species and the central nervous system. J Neurochem 59(5): 1609–1623
Hare B, Plysunia I, Ignacio N, Schepina O, Stepika A and Wrangham R et al. (2005) Social cognitive evolution in captive foxes is a correlated by-product of experimental domestication. Curr Biol 15(3): 226–230
Hashimoto M, Hossain S, Shimada T, Sugioka K, Yamasaki H and Fujii Y et al. (2002) Docosahexaenoic acid provides protection from impairment of learning ability in Alzheimer’s disease model rats. J Neurochem 81(5): 1084–1091
Head E, Mehta R, Hartley J, Kameka M, Cummings BJ and Cotman CW et al. (1995) Spatial learning and memory as a function of age in the dog. Behav Neurosci 109(5): 851–858
Head E, Callahan H, Muggenburg BA, Cotman CW and Milgram NW (1998) Visual-discrimination learning ability and beta-amyloid accumulation in the dog. Neurobiol Aging 19(5): 415–425
Head E, McCleary R, Hahn FF, Milgram NW and Cotman CW (2000) Region-specific age at onset of beta-amyloid in dogs. Neurobiol Aging 21(1): 89–96
Head E, Liu J, Hagen TM, Muggenburg BA, Milgram NW and Ames BN et al. (2002) Oxidative damage increases with age in a canine model of human brain aging. J Neurochem 82(2): 375–381
Head E, Tapp PD, Milgram NW, Moffat K, Landberg G and Su M-Y (2004) Neurobiology of aging in dogs and cats. In: Conference Proceedings of the American College of Veterinary Internal Medicine (http://www.vin.com/Members/Proceedings/)
Helmer C, Peuchant E, Letenneur L, Bourdel-Marchasson I, Larrieu S and Dartigues JF et al. (2003) Association between antioxidant nutritional indicators and the incidence of dementia: results from the PAQUID prospective cohort study. Eur J Clin Nutr 57(12): 1555–1561
Horrocks LA and Yeo YK (1999) Health benefits of docosahexaenoic acid (DHA). Pharmacol Res 40(3): 211–225
Huber T, Rajamoorthi K, Kurze VF, Beyer K and Brown MF (2002) Structure of docosahexaenoic acid-containing phospholipid bilayers as studied by (2)H NMR and molecular dynamics simulations. J Am Chem Soc 124(2): 298–309
Jama JW, Launer LJ, Witteman JC, den Breeijen JH, Breteler MM and Grobbee DE et al. (1996) Dietary antioxidants and cognitive function in a population-based sample of older persons. The Rotterdam Study. Am J Epidemiol 144(3): 275–280
Jernigan TL, Archibald SL, Fennema-Notestine C, Gamst AC, Stout JC and Bonner J et al. (2001) Effects of age on tissues and regions of the cerebrum and cerebellum. Neurobiol Aging 22(4): 581–894
Joseph JA, Shukitt-Hale B, Denisova NA, Prior RL, Cao G and Martin A et al. (1998) Long-term dietary strawberry, spinach, or vitamin E supplementation retards the onset of age-related neuronal signal-transduction and cognitive behavioral deficits. J Neurosci 18(19): 8047–8055
Joseph JA, Shukitt-Hale B, Denisova NA, Bielinski D, Martin A and McEwen JJ et al. (1999) Reversals of age-related declines in neuronal signal transduction, cognitive, and motor behavioral deficits with blueberry, spinach, or strawberry dietary supplementation. J Neurosci 19: 8114–8121
Koenig BW, Strey HH and Gawrisch K (1997) Membrane lateral compressibility determined by NMR and X-ray diffraction: effect of acyl chain polyunsaturation. Biophys J 73(4): 1954–1966
Kyle DJ, Schaefer E, Patton G and Beiser A (1999) Low serum docosahexaenoic acid is a significant risk factor for Alzheimer’s dementia. Lipids 34(Suppl): S245
Lafora G (1914) Neoformaciones dentriticas an las neuronas y alteraciones de la neuroglia en el perro senil. Trab Lab Investig Biol t.12: FaSc.1
Landsberg G and Ruehl W (1997) Geriatric behavioral problems. Vet Clin North, Small Anim Pract 27(6): 1537–1559
Larrieu S, Letenneur L, Orgogozo JM, Fabrigoule C, Amieva H and Le Carret N et al. (2002) Incidence and outcome of mild cognitive impairment in a population-based prospective cohort. Neurology 59(10): 1594–1599
Laurin D, Masaki KH, Foley DJ, White LR and Launer LJ (2004) Midlife dietary intake of antioxidants and risk of late-life incident dementia: the Honolulu–Asia Aging Study. Am J Epidemiol 159(10): 959–967
Lindeman RD, Romero LJ, Koehler KM, Liang HC, LaRue A and Baumgartner RN et al. (2000) Serum vitamin B12, C and folate concentrations in the New Mexico elder health survey: correlations with cognitive and affective functions. J Am Coll Nutr 19(1): 68–76
Luchsinger JA, Tang MX, Shea S and Mayeux R (2003) Antioxidant vitamin intake and risk of Alzheimer disease. Arch Neurol 60(2): 203–208
Martin A (2003) Antioxidant vitamins E and C and risk of Alzheimer’s disease. Nutr Rev 61(2): 69–73
Martin A, Cherubini A, Andres-Lacueva C, Paniagua M and Joseph J (2002) Effects of fruits and vegetables on levels of vitamins E and C in the brain and their association with cognitive performance. J Nutr Health Aging 6(6): 392–404
Masaki KH, Losonczy KG, Izmirlian G, Foley DJ, Ross GW and Petrovitch H et al. (2000) Association of vitamin E and C supplement use with cognitive function and dementia in elderly men. Neurology 54(6): 1265–1272
McDaniel MA, Maier SF and Einstein GO (2003) “Brain-specific” nutrients: a memory cure? Nutrition 19(11–12): 957–975
Mendelsohn AB, Belle SH, Stoehr GP and Ganguli M (1998) Use of antioxidant supplements and its association with cognitive function in a rural elderly cohort: the MoVIES Project. Monongahela Valley Independent Elders Survey. Am J Epidemiol 148(1): 38–44
Milgram NW (2003) Cognitive experience and its effect on age-dependent cognitive decline in beagle dogs. Neurochem Res 28(11): 1677–1682
Milgram NW, Head E, Weiner E and Thomas E (1994) Cognitive functions and aging in the dog: acquisition of nonspatial visual tasks. Behav Neurosci 108(1): 57–68
Milgram NW, Adams B, Callahan H, Head E, Mackay B and Thirlwell C et al. (1999) Landmark discrimination learning in the dog. Learn Mem 6(1): 54–61
Milgram NW, Head E, Muggenburg B, Holowachuk D, Murphey H and Estrada J et al. (2002a) Landmark discrimination learning in the dog: effects of age, an antioxidant fortified food, and cognitive strategy. Neurosci Biobehav Rev 26(6): 679–695
Milgram NW, Zicker SC, Head E, Muggenburg BA, Murphey H and Ikeda-Douglas CJ et al. (2002b) Dietary enrichment counteracts age-associated cognitive dysfunction in canines. Neurobiol Aging 23(5): 737–745
Milgram NW, Head E, Zicker SC, Ikeda-Douglas C, Murphey H and Muggenberg BA et al. (2004) Long-term treatment with antioxidants and a program of behavioral enrichment reduces age-dependent impairment in discrimination and reversal learning in beagle dogs. Exp Gerontol 39(5): 753–765
Milgram NW, Head E, Zicker SC, Ikeda-Douglas CJ, Murphey H and Muggenburg B et al. (2005) Learning ability in aged beagle dogs is preserved by behavioral enrichment and dietary fortification: a two-year longitudinal study. Neurobiol Aging 26(1): 77–90
Morris MC, Evans DA, Bienias JL, Tangney CC, Bennett DA and Wilson RS et al. (2003) Consumption of fish and n-3 fatty acids and risk of incident Alzheimer disease. Arch Neurol 60(7): 940–946
Osetowska E (1966) Morphologic changes in the brains of old dogs. Neuropatol Pol 4(1): 97–110
Papaioannou N, Tooten PC, van Ederen AM, Bohl JR, Rofina J and Tsangaris T et al. (2001) Immunohistochemical investigation of the brain of aged dogs. I. Detection of neurofibrillary tangles and of 4-hydroxynonenal protein, an oxidative damage product, in senile plaques. Amyloid 8(1): 11–21
Prior R, D’Urso D, Frank R, Prikulis I, Wihl G and Pavlakovic G (1996) Canine leptomeningeal organ culture: a new experimental model for cerebrovascular beta-amyloidosis. J Neurosci Methods 68(2): 143–148
Resnick SM, Goldszal AF, Davatzikos C, Golski S, Kraut MA and Metter EJ et al. (2000) One-year age changes in MRI brain volumes in older adults. Cereb Cortex 10(5): 464–472
Ruehl WW, Bruyette DS, DePaoli A, Cotman CW, Head E and Milgram NW et al. (1995) Canine cognitive dysfunction as a model for human age-related cognitive decline, dementia and Alzheimer’s disease: clinical presentation, cognitive testing, pathology and response to l-deprenyl therapy. In: Yu PM, Tipton KF and Boulton AA (eds) Progress in Brain Research, Vol. 106, Chapter 22, 217–225. Elsevier, Amsterdam
Satou T, Cummings BJ, Head E, Nielson KA, Hahn FF and Milgram NW et al. (1997) The progression of beta-amyloid deposition in the frontal cortex of the aged canine. Brain Res 774(1–2): 35–43
Sharma D, Maurya AK and Singh R (1993) Age-related decline in multiple unit action potentials of CA3 region of rat hippocampus: correlation with lipid peroxidation and lipofuscin concentration and the effect of centrophenoxine. Neurobiol Aging 14(4): 319–330
Shigenaga MK, Hagen TM and Ames BN (1994) Oxidative damage and mitochondrial decay in aging. Proc Nat Acad Sci USA 91(23): 10771–10778
Siwak CT, Tapp PD and Milgram NW (2001) Effect of age and level of cognitive function on spontaneous and exploratory behaviors in the beagle dog. Learn Mem 8(6): 317–325
Siwak CT, Tapp PD, Zicker SC, Murphey HL, Muggenburg BA and Head E et al. (2003) Locomotor activity rhythms in dogs vary with age and cognitive status. Behav Neurosci 117(4): 813–824
Stuss DT, Craik FI, Sayer L, Franchi D and Alexander MP (1996) Comparison of older people and patients with frontal lesions: evidence from world list learning. Psychol Aging 11(3): 387–395
Su MY, Head E, Brooks WM, Wang Z, Muggenburg BA and Adam GE et al. (1998) Magnetic resonance imaging of anatomic and vascular characteristics in a canine model of human aging. Neurobiol Aging 19(5): 479–485
Tapp PD, Siwak CT, Estrada J, Head E, Muggenburg BA and Cotman CW et al. (2003a) Size and reversal learning in the beagle dog as a measure of executive function and inhibitory control in aging. Learn Mem 10(1): 64–73
Tapp PD, Siwak CT, Estrada J, Holowachuk D and Milgram NW (2003) Effects of age on measures of complex working memory span in the beagle dog (Canis familiaris) using two versions of a spatial list learning paradigm. Learn Mem 10(2): 148–160
Tapp PD, Siwak CT, Gao FQ, Chiou JY, Black SE and Head E et al. (2004a) Frontal lobe volume, function, and beta-amyloid pathology in a canine model of aging. J Neurosci 24(38): 8205–8213
Tapp PD, Siwak CT, Head E, Cotman CW, Murphey H and Muggenburg BA et al. (2004b) Concept abstraction in the aging dog: development of a protocol using successive discrimination and size concept tasks. Behav Brain Res 153(1): 199–210
Thomas RK (1996) Investigating cognitive abilities in animals: unrealized potential. Cogn Brain Res 3(3–4): 157–166
Tully AM, Roche HM, Doyle R, Fallon C, Bruce I and Lawlor B et al. (2003) Low serum cholesteryl ester-docosahexaenoic acid levels in Alzheimer’s disease: a case-control study. Br J Nutr 89(4): 483–489
Voytko ML (1999) Impairments in acquisition and reversals of two-choice discriminations by aged rhesus monkeys. Neurobiol Aging (6): 617–627
Walker LC (1997) Animal models of cerebral beta-amyloid angiopathy. Brain Res-Brain Res Rev 25(1): 70–84
Wegiel J, Wisniewski HM and Soltysiak Z (1998) Region- and cell-type-specific pattern of tau phosphorylation in dog brain. Brain Res 802(1–2): 259–266
Zandi PP, Anthony JC, Khachaturian AS, Stone SV, Gustafson D and Tschanz JT et al. (2004) Reduced risk of Alzheimer disease in users of antioxidant vitamin supplements: the Cache County Study. Arch Neurol 61(1): 82–88
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Araujo, J.A., Studzinski, C.M., Head, E. et al. Assessment of nutritional interventions for modification of age-associated cognitive decline using a canine model of human aging. AGE 27, 27–37 (2005). https://doi.org/10.1007/s11357-005-4001-z
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DOI: https://doi.org/10.1007/s11357-005-4001-z