A 60-month follow-up of a naturalistic study of integrative treatment for real-life geriatric patients with depression, dementia and multiple chronic illnesses


Background: In the past we have shown the preservation and improvement of cognitive tasks in depressed and demented patients after 24 and 36 months of combined pharmacological and non-pharmacological treatment. Here we present the results of our ongoing, naturalistic study, in the same outpatient setting, at 60 month follow up. Materials and Methods: The study group consisted of 156 medically ill, physically disabled patients with mild to moderate dementia and depression. Patients were treated with antidepressants, cholinesterase inhibitors, and NMDA antagonists, along with their regular medication regimen. Non-pharmacological intervention was centered on a home-based program of physical and cognitive exercises paired with vitamins and supplements (multivitamins, vitamin E, L-methylfolate, alphalipoic acid, acetyl-L-carnitine, omega-3, and coenzyme Q-10) and diet modification. Cognitive assessments were performed yearly. Results: After 60 months of treatment, performance of all tasks remained at or above baseline. The MMSE, Cognistat-Attention, Cognistat-Judgment, and RFFT-Total Unique Designs demonstrated significant improvement. Conclusion: Our results, for the first time, demonstrate arrest in cognitive decline in demented/depressed patients with multiple medical co-morbidities for 60 months. Future investigations addressing the application of a combined, integrative treatment model are warranted.

Share and Cite:

Bragin, V. , Chemodanova, M. , Bragin, I. , Dzhafarova, N. , Mescher, I. , Chernyavskyy, P. , E. Obrenovich, M. , H. Palacios, H. and Aliev, G. (2012) A 60-month follow-up of a naturalistic study of integrative treatment for real-life geriatric patients with depression, dementia and multiple chronic illnesses. Open Journal of Psychiatry, 2, 129-140. doi: 10.4236/ojpsych.2012.22018.

Conflicts of Interest

The authors declare no conflicts of interest.


[1] Aliev, G., Palacios, H.H., Lipsitt, A.E., Fischbach, K., Lamb, B.T., Obrenovich, M.E., Morales, L., Gasimov, E. and Bragin, V. (2009) Nitric oxide as an initiator of brain lesions during the development of Alzheimer disease. Neurotoxicity Research, 16, 293-305. doi:10.1007/s12640-009-9066-5
[2] Daulatzai, M.A. (2010) Early stages of pathogenesis in memory impairment during normal senescence and Alzheimer’s disease. Journal of Alzheimer’s Disease, 20, 355-367.
[3] De La Torre, J.C. (2008) Pathophysiology of neuronal energy crisis in Alzheimer’s disease. Neurodegenerative Diseases, 5, 126-132. doi:10.1159/000113681
[4] Swerdlow, R.H. (2007) Pathogenesis of Alzheimer’s disease. Journal of Clinical Interventions in Aging, 2, 347-359.
[5] Weller, R.O., Subash, M., Preston, S.D., Mazanti, I. and Carare, R.O. (2008) Perivascular drainage of amyloidbeta peptides from the brain and its failure in cerebral amyloid angiopathy and Alzheimer’s disease. Brain Pathology, 18, 253-266. doi:10.1111/j.1750-3639.2008.00133.x
[6] Querfurth, H.W. and LaFerla, F.M. (2010) Alzheimer’s disease. The New England Journal of Medicine, 362, 329-344. doi:10.1056/NEJMra0909142
[7] Swerdlow, R.H. and Khan, S.M. (2009) The Alzheimer’s disease mitochondrial cascade hypothesis: An update. Experimental Neurology, 218, 308-315. doi:10.1016/j.expneurol.2009.01.011
[8] Helzner, E.P., Luchsinger, J.A., Scarmeas, N., Cosentino, S., Brickman, A.M., Glymour, M.M. and Stern, Y. (2009) Contribution of vascular risk factors to the progression in Alzheimer disease. Archives of Neurology, 66, 343-348. doi:10.1001/archneur.66.3.343
[9] Hanada, K., Hosono, M., Kudo, T., Hitomi, Y., Yagyu, Y., Kirime, E., Komeya, Y., Tsujii, N., Hitomi, K. and Nishimura, Y. (2006) Regional cerebral blood flow in the assessment of major depression and Alzheimer’s disease in the early elderly. Nuclear Medicine Communications, 27, 535-541. doi:10.1097/00006231-200606000-00010
[10] Nobler, M.S., Pelton, G.H. and Sackeim, H.A. (1999) Cerebral blood flow and metabolism in late-life depression and dementia. Journal of Geriatric Psychiatry and Neurology, 12, 118-127. doi:10.1177/089198879901200305
[11] Henry-Feugeas, M.C. (2009) Assessing cerebrovascular contribution to late dementia of the Alzheimer’s type: The role of combined hemodynamic and structural MR analysis. Journal of the Neurological Sciences, 283, 44-48. doi:10.1016/j.jns.2009.02.325
[12] Johnson, N.A., Jahng, G.H., Weiner, M.W., Miller, B.L., Chui, H.C., Jagust, W.J., Gorno-Tempini, M.L. and Schuff, N. (2005) Pattern of cerebral hypoperfusion in Alzheimer disease and mild cognitive impairment measured with arterial spin-labeling MR imaging: Initial experience. Radiology, 234, 851-859. doi:10.1148/radiol.2343040197
[13] Kataoka, K., Hashimoto, H., Kawabe, J., Higashiyama, S., Akiyama, H., Shimada, A., Kai, T., Inoue, K., Shiomi, S. and Kiriike, N. (2010) Frontal hypoperfusion in de- pressed patients with dementia of Alzheimer type demonstrated on 3DSRT. Psychiatry and Clinical Neurosciences, 64, 293-298. doi:10.1111/j.1440-1819.2010.02083.x
[14] Prins, N. D., Van Straaten, E.C., van Dijk, E.J., Simoni, M., van Schijndel, R.A., Vrooman, H.A., Koudstaal, P.J., Scheltens, P., Breteler, M.M. and Barkhof, F. (2004) Measuring progression of cerebral white matter lesions on MRI: Visual rating and volumetrics. Neurology, 62, 1533-1539.
[15] Peers, C., Dallas, M.L., Boycott, H.E., Scragg, J.L., Pearson, H.A. and Boyle, J.P. (2009) Hypoxia and neurodegeneration. Annals of the New York Academy of Sciences, 1177, 169-177. doi:10.1111/j.1749-6632.2009.05026.x
[16] Peers, C., Pearson, H.A. and Boyle, J.P. (2007) Hypoxia and Alzheimer’s disease. Essays in Biochemistry, 43, 153-164. doi:10.1042/BSE0430153
[17] Zhang, X. and Le, W., (2010) Pathological role of hypoxia in Alzheimer’s disease. Experimental Neurology, 223, 299-303. doi:10.1016/j.expneurol.2009.07.033
[18] Prins, N.D., van Dijk, E.J., den Heijer, T., Vermeer, S.E., Koudstaal, P.J., Oudkerk, M., Hofman, A. and Breteler, M.M. (2004) Cerebral white matter lesions and the risk of dementia. Archives of Neurology, 61, 1531-1534. doi:10.1001/archneur.61.10.1531
[19] Bennett, S., Grant, M.M. and Aldred, S. (2009) Oxidative stress in vascular dementia and Alzheimer’s disease: A common pathology. Journal of Alzheimer’s Disease, 17, 245-257.
[20] Aliev, G., Palacios, H.H., Walrafen, B., Lipsitt, A.E., Obrenovich, M.E. and Morales, L. (2009) Brain mitochondria as a primary target in the development of treatment strategies for Alzheimer disease. The International Journal of Biochemistry & Cell Biology, 41, 1989-2004. doi:10.1016/j.biocel.2009.03.015
[21] Andrade, C. and Radhakrishnan, R. (2009) The prevention and treatment of cognitive decline and dementia: An overview of recent research on experimental treatments. Indian Journal of Psychiatry, 51, 12-25.
[22] Acevedo, A. and Loewenstein, D.A. (2007) Nonpharmacological cognitive interventions in aging and dementia. Journal of Geriatric Psychiatry and Neurology, 20, 239-249. doi:10.1177/0891988707308808
[23] Adamsa, J., Luia, C. and McLaughlina, D. (2009) The use of complementary and alternative medicine in later life. Reviews in Clinical Gerontology, Cambridge University Press, Cambridge, 227-236.
[24] Goh, J.O. and Park, D.C. (2009) Neuroplasticity and cognitive aging: The scaffolding theory of aging and cognition. Restorative Neurology and Neuroscience, 27, 391-403.
[25] Kuo, M.F., Grosch, J., Fregni, F., Paulus, W. and Nitsche, M.A. (2007) Focusing effect of acetylcholine on neuroplasticity in the human motor cortex. The Journal of Neuroscience, 27, 14442-14447. doi:10.1523/JNEUROSCI.4104-07.2007
[26] Middleton, L.E. and Yaffe, K. (2010) Targets for the prevention of dementia. Journal of Alzheimer’s Disease, 20, 915-924.
[27] Zec, R.F. and Burkett, N.R. (2008) Non-pharmacological and pharmacological treatment of the cognitive and behavioral symptoms of Alzheimer disease. NeuroRehabilitation, 23, 425-438.
[28] Burns, A., Gauthier, S. and Perdomo, C. (2007) Efficacy and safety of donepezil over 3 years: An open-label, multicentre study in patients with Alzheimer’s disease. International Journal of Geriatric Psychiatry, 22, 806-812. doi:10.1002/gps.1746
[29] Persson, C.M., Wallin, A.K., Levander, S. and Minthon, L. (2009) Changes in cognitive domains during three years in patients with Alzheimer’s disease treated with donepezil. BMC Neurology, 9, 7. doi:10.1186/1471-2377-9-7
[30] Bottino, C.M., Carvalho, I.A., Alvarez, A.M., Avila, R., Zukauskas, P.R., Bustamante, S.E., Andrade, F.C., Hototian, S.R., Saffi, F. and Camargo, C.H. (2005) Cognitive rehabilitation combined with drug treatment in Alzheimer’s disease patients: A pilot study. Clinical Rehabilitation, 19, 861-869. doi:10.1191/0269215505cr911oa
[31] Rozzini, L., Costardi, D., Chilovi, B.V., Franzoni, S., Trabucchi, M. and Padovani, A. (2007) Efficacy of cognitive rehabilitation in patients with mild cognitive impairment treated with cholinesterase inhibitors. International Journal of Geriatric Psychiatry, 22, 356-360. doi:10.1002/gps.1681
[32] Chan, A., Paskavitz, J., Remington, R., Rasmussen, S. and Shea, T.B. (2008) Efficacy of a vitamin/nutriceutical formulation for early-stage Alzheimer’s disease: A 1-year, open-label pilot study with an 16-month caregiver extension. American Journal of Alzheimer’s Disease and Other Dementias, 23, 571-585. doi:10.1177/1533317508325093
[33] Heyn, P. (2003) The effect of a multisensory exercise program on engagement, behavior, and selected physiological indexes in persons with dementia. American Journal of Alzheimer’s Disease and Other Dementias, 18, 247-251. doi:10.1177/153331750301800409
[34] Yu, F., Kolanowski, A.M., Strumpf, N.E. and Eslinger, P.J. (2006) Improving cognition and function through exercise intervention in Alzheimer’s disease. Journal of Nursing Scholarship, 38, 358-365. doi:10.1111/j.1547-5069.2006.00127.x
[35] Bragin, V., Chemodanova, M., Dzhafarova, N., Bragin, I., Czerniawski, J.L. and Aliev, G. (2005) Integrated treatment approach improves cognitive function in demented and clinically depressed patients. American Journal of Alzheimer’s Disease and Other Dementias, 20, 21-26. doi:10.1177/153331750502000103
[36] Bragin, V., Chemodanova, M., Dzhafarova, N., Bragin, I., Chernyavskyy, P. and Aliev, G. (2009) Preservation of cognitive functioning in depressed, demented geriatric patients with cardiovascular risk factors: An ongoing 3-year naturalistic study. Alzheimer’s & Dementia, 5, 320. doi:10.1016/j.jalz.2009.04.517
[37] Bragin, V. (2007) How to activate your brain. Au- thorhouse, Bloominton.
[38] Bragin, V., Chemodanova, M., Vaysman, V., Bragin, I., Chernyavskyy, P., Grinayt, E. and Aliev, G. (2009) Preservation of learning abilities in people with dementia and depression with different level of cognitive impairment. Alzheimer’s & Dementia, 5, 322. doi:10.1016/j.jalz.2009.04.523
[39] Bragin, V., Chemodanova, M., Vaysman, V., Bragin, I., Grinayt, E. and Ruditser, M. (2008) N-back task to tailor memory training protocols for patients with depression and dementia. Alzheimer’s Association International Conference on Alzheimer’s Disease, Chicago, 26-31 July 2008, 496-497.
[40] Folstein, M.F., Folstein, S.E. and McHugh, P.R. (1975) “Mini-mental state.” A practical method for grading the cognitive state of patients for the clinician. Journal of Psychiatric Research, 12, 189-198. doi:10.1016/0022-3956(75)90026-6
[41] Kiernan, R., Mueller, J. and Langston, W., (2002) Cognistat (neurobehavioral cognitive status examination). Psychological Assessment Resources, Odessa, FLA.
[42] Ruff, R. and Allen, C. (2002) Ruff 2 & 7 selective attention test. Psychological Assessment Resources, Odessa.
[43] Ruff, R. (2002) Ruff Figural Fluency Test (RFFT). Psychological Assessment Resources, Odessa.
[44] SPSS Base 17 Applications Guide (2009) SPSS Inc., Chicago.
[45] Hall, C.B., Lipton, R.B., Sliwinski, M., Katz, M.J., Derby, C.A. and Verghese, J. (2009) Cognitive activities delay onset of memory decline in persons who develop dementia. Neurology, 73, 356-361. doi:10.1212/WNL.0b013e3181b04ae3
[46] Middleton, L.E. and Yaffe, K. (2009) Promising strategies for the prevention of dementia. Archives of Neurology, 66, 1210-1215. doi:10.1001/archneurol.2009.201
[47] Aliev G., Li, Y., Palacios, H.H. and Obrenovich, M.E. (2011) Oxidative stress induced mitochondrial DNA deletion as a hallmark for the drug development in the context of the cerebrovascular diseases. Recent Patents on Cardiovascular Drug Discovery, 6, 222-241.
[48] Kobayashi, S., Tateno, M., Utsumi, K., Takahashi, A., Saitoh, M., Morii, H., Fujii, K. and Teraoka, M. (2008) Quantitative analysis of brain perfusion SPECT in Alzheimer’s disease using a fully automated regional cerebral blood flow quantification software, 3DSRT. Journal of the Neurological Sciences, 264, 27-33. doi:10.1016/j.jns.2007.07.015
[49] Aliev, G., Liu, J., Shenk, J.C., Fischbach, K., Pacheco, G.J., Chen, S.G., Obrenovich, M.E., Ward, W.F., Richardson, A.G., Smith, M. A.; Gasimov, E., Perry, G. and Ames, B.N. (2009) Neuronal mitochondrial amelioration by feeding acetyl-L-carnitine and lipoic acid to aged rats. Journal of Cellular and Molecular Medicine, 13, 320-333. doi:10.1111/j.1582-4934.2008.00324.x
[50] Milgram, N.W., Araujo, J.A., Hagen, T.M., Treadwell, B.V. and Ames, B.N. (2007) Acetyl-L-carnitine and alpha-lipoic acid supplementation of aged beagle dogs improves learning in two landmark discrimination tests. The FASEB Journal, 21, 3756-3762. doi:10.1096/fj.07-8531com
[51] Head, E., Nukala, V.N., Fenoglio, K.A., Muggenburg, B.A., Cotman, C.W. and Sullivan, P.G. (2009) Effects of age, dietary, and behavioral enrichment on brain mitochondria in a canine model of human aging. Experimental Neurology, 220, 171-176. doi:10.1016/j.expneurol.2009.08.014
[52] Pop, V., Head, E., Hill, M.A., Gillen, D., Berchtold, N.C., Muggenburg, B.A., Milgram, N.W., Murphy, M.P. and Cotman, C.W. (2010) Synergistic effects of long-term antioxidant diet and behavioral enrichment on beta-amyloid load and non-amyloidogenic processing in aged canines. The Journal of Neuroscience, 30, 9831-9839. doi:10.1523/JNEUROSCI.6194-09.2010
[53] Manukhina, E.B., Goryacheva, A.V., Barskov, I.V., Viktorov, I.V., Guseva, A.A., Pshennikova, M.G., Khomenko, I.P., Mashina, S.Y., Pokidyshev, D.A. and Malyshev, I.Y. (2010) Prevention of neurodegenerative damage to the brain in rats in experimental Alzheimer’s disease by adaptation to hypoxia. Neuroscience and Behavioral Physiology, 40, 737-743. doi:10.1007/s11055-010-9320-6
[54] Shenk, J.C., Liu, J., Fischbach, K., Xu, K., Puchowicz, M., Obrenovich, M.E., Gasimov, E., Alvarez, L.M., Ames, B.N., Lamanna, J.C. and Aliev, G. (2009) The effect of acetyl-L-carnitine and R-alpha-lipoic acid treatment in ApoE4 mouse as a model of human Alzheimer’s disease. Journal of the Neurological Sciences, 283, 199-206. doi:10.1016/j.jns.2009.03.002
[55] Black, J.E., Sirevaag, A.M. and Greenough, W.T. (1987) Complex experience promotes capillary formation in young rat visual cortex. Neuroscience Letters, 83, 351-355. doi:10.1016/0304-3940(87)90113-3
[56] Brown, J., Cooper-Kuhn, C.M., Kempermann, G., Van Praag, H., Winkler, J., Gage, F.H. and Kuhn, H.G. (2003) Enriched environment and physical activity stimulate hippocampal but not olfactory bulb neurogenesis. European Journal of Neuroscience, 17, 2042-2046. doi:10.1046/j.1460-9568.2003.02647.x
[57] Cracchiolo, J.R., Mori, T., Nazian, S.J., Tan, J., Potter, H. and Arendash, G.W. (2007) Enhanced cognitive activeity—Over and above social or physical activity—Is required to protect Alzheimer's mice against cognitive impairment, reduce Abeta deposition, and increase synaptic immunoreactivity. Neurobiology of Learning and Memory, 88, 277-294. doi:10.1016/j.nlm.2007.07.007
[58] Requena, C., Maestu, F., Campo, P., Fernandez, A. and Ortiz, T. (2006) Effects of cholinergic drugs and cognitive training on dementia: 2-year follow-up. Dementia and Geriatric Cognitive Disorders, 22, 339-345. doi:10.1159/000095600
[59] Chapman, S.B., Weiner, M.F., Rackley, A., Hynan, L.S. and Zientz, J. (2004) Effects of cognitive-communication stimulation for Alzheimer’s disease patients treated with donepezil. Journal of Speech, Language, and Hearing Research, 47, 1149-1163. doi:10.1044/1092-4388(2004/085)
[60] Eckroth-Bucher, M. and Siberski, J. (2009) Preserving cognition through an integrated cognitive stimulation and training program. American Journal of Alzheimer’s Disease and Other Dementias, 24, 234-245. doi:10.1177/1533317509332624
[61] Kawashima, R., Itoh, H., Ono, S., Satoh, K., Furumoto, S., Gotoh, R., Koyama, M., Yoshioka, S., Takahashi, T., Takahashi, K., Yanagisawa, T. and Fukuda, H. (1996) Changes in regional cerebral blood flow during self-paced arm and finger movements. A PET study. Brain Research, 716, 141-148. doi:10.1016/0006-8993(96)00032-7
[62] Kawashima, R., Matsumura, M., Sadato, N., Naito, E., Waki, A., Nakamura, S., Matsunami, K., Fukuda, H. and Yonekura, Y. (1998) Regional cerebral blood flow changes in human brain related to ipsilateral and contralateral complex hand movements—A PET study. European Journal of Neuroscience, 10, 2254-2260. doi:10.1046/j.1460-9568.1998.00237.x
[63] Khalsa, D.S., Amen, D., Hanks, C., Money, N. and Newberg, A. (2009) Cerebral blood flow changes during chanting meditation. Nuclear Medicine Communications, 30, 956-961. doi:10.1097/MNM.0b013e32832fa26c
[64] Roland, P.E., Meyer, E., Shibasaki, T., Yamamoto, Y.L. and Thompson, C.J. (1982) Regional cerebral blood flow changes in cortex and basal ganglia during voluntary movements in normal human volunteers. Journal of Neurophysiology, 48, 467-480.
[65] Van Mier, H., Tempel, L.W., Perlmutter, J.S., Raichle, M.E. and Petersen, S.E. (1998) Changes in brain activity during motor learning measured with PET: Effects of hand of performance and practice. Journal of Neurophysiology, 80, 2177-2199.
[66] Mozolic, J.L., Hayasaka, S. and Laurienti, P.J. (2010) A cognitive training intervention increases resting cerebral blood flow in healthy older adults. Frontiers in Human Neuroscience, 4, 16. doi:10.3389/neuro.09.016.2010
[67] Bragin, V. and Aliev, G. (2010) Progression of cognitive function after integrated treatment approach in demented and clinically depressed patients. In: Aliev G., et al., Eds., The Role of Oxidative Stress, Mitochondria Failure and Cellular Hypoperfusion in the Pathobiology of Alzheimer Disease, Research Signpost, Inc., Trivandrum, 317-325.
[68] Palacios, H.H., Yendluri, B.B., Parvathaneni, K., Shadlinski, V.B., Obrenovich, M.E., Leszek, J., Gokhman, D., Gasiorowski, K., Bragin, V. and Aliev, G. (2011) Mitochondrion-specific antioxidants as drug treatments for Alzheimer disease. CNS & Neurological Disorders— Drug Targets, 10, 149-162.
[69] Aliev, G. (2011) Oxidative stress induced-metabolic imbalance, mitochondrial failure, and cellular hypoperfusion as primary pathogenetic factors for the development of Alzheimer disease which can be used as a alternate and successful drug treatment strategy: Past, present and future. CNS & Neurological Disorders—Drug Targets, 10, 147-148.

Copyright © 2023 by authors and Scientific Research Publishing Inc.

Creative Commons License

This work and the related PDF file are licensed under a Creative Commons Attribution 4.0 International License.