Abstract
Retrogenesis is the process by which degenerative mechanisms reverse the order of acquisition in normal development. Alzheimer's disease (AD) and related conditions in the senium have long been noted to resemble “a return to childhood.” Previously, we noted that the functional stages of AD precisely and remarkably recapitulated the acquisition of the same functional landmarks in normal human development. Subsequent work indicated that this developmental recapitulation also applied to the cognitive and related symptoms in AD. Remarkably, further investigations revealed that the same neurologic “infantile” reflexes, which mark the emergence from infancy in normal development, are equally robust indicators of corresponding stages in AD. Neuropathologic and biomolecular mechanisms for these retrogenic processes are now evident. For example, the pattern of myelin loss in AD appears to mirror the pattern of myelin acquisition in normal development. Also, recent findings indicate that mitogenic factors become reactivated in AD, and, consequently, the most actively “growing” brain regions are the most vulnerable. Because of this robust retrogenic process, the stages of AD can be translated into corresponding developmental ages (DAs). These DAs can account for the overall management and care needs of AD patients. A science of AD management can be formulated on the basis of the DA of the Alzheimer's patient, taking into consideration differences of AD from normal development as well as homologies.
Keywords: Alzheimer's disease, care concepts, dementia, dementia management, retrogenesis
Full Text
The Full Text of this article is available as a PDF (126.8 KB).
Contributor Information
Barry Reisberg, Zachary and Elizabeth M. Fisher Alzheimer's Disease Education and Resources Program; William and Sylvia Silberstein Aging and Dementia Research Center; Department of Psychiatry, New York University School of Medicine, New York, New York..
Liduïn E.M. Souren, Zachary and Elizabeth M. Fisher Alzheimer's Disease Education and Resources Program and the William and Sylvia Silberstein Aging and Dementia Research Center, New York University School of Medicine, New York, New York..
Stefanie R. Auer, Science and Development, Verein M.A.S. Bad Ischl, Austria..
Imran Akram, Zachary and Elizabeth M. Fisher Alzheimer's Disease Education and Resources Program and the William and Sylvia Silberstein Aging and Dementia Research Center, New York University School of Medicine, New York, New York..
Sunnie Kenowsky, Zachary and Elizabeth M. Fisher Alzheimer's Disease Education and Resources Program, New York University School of Medicine, New York, New York..
References
- Reisberg B, Franssen EH, Hasan SM, et al.: Retrogenesis: Clinical, physiologic and pathologic mechanisms in brain aging, Alzheimer's and other dementing processes. European Archives of Psychiatry and Clinical Neuroscience. 1999; 249 (Suppl 3): 28-36. [DOI] [PubMed] [Google Scholar]
- Aristophanes: The Clouds. In Oates WJ, O'Neil E (eds.): The Complete Greek Drama. New York: Random House, 1938. [translation]: 595-595. [Google Scholar]
- Shakespeare W: “As you like it,” Act 2, Scene 7. In Wells S, Taylor G (eds.): William Shakespeare: The Complete Works. (Compact Ed.) Oxford: Oxford University Press, 1988: 638-638. [Google Scholar]
- Rush B: An account of the state of mind and body in old age. In: Rush B (ed.): Medical Inquiries and Observations. Philadelphia: Dobson, 1793: 311-311. [Google Scholar]
- de Ajuriaguerra J, Rey M, Bellet-Muller M: A propos de quelques problems posees par le deficit operatoire des viellards atteints de demence degenerative en debut d’evolution. Cortex. 1964; 1: 232-256. [Google Scholar]
- de Ajuriaguerra J, Tissot R: Some aspects of psychoneurologic disintegration in senile dementia. In Mueller CH, Ciompi L (eds.): Senile Dementia. Switzerland: Huber, 1968: 69-79. [Google Scholar]
- de Ajuriaguerra J, Tissot R: Some aspects of language in various forms of senile dementia (comparisons with language in childhood). In Lennenberg EH, Lennenberg E (eds.): Foundations of Language Development (Vol. 1). New York: Academic Press, 1975: 323-339. [Google Scholar]
- Reisberg B, Ferris SH, Anand R, et al.: Functional staging of dementia of the Alzheimer's type. Annals of the New York Academy of Sciences. 1984; 435: 481-483. [Google Scholar]
- Reisberg B: Functional assessment staging (FAST). Psychopharmacology Bulletin. 1988; 24: 653-659. [PubMed] [Google Scholar]
- Reisberg B, Ferris SH, Franssen E: Functional degenerative stages in dementia of the Alzheimer's type appear to reverse normal human development. In Shagass C, Josiassen R, Bridger WH, et al. (eds.): Biological Psychiatry, 1985. (Vol. 7). New York: Elsevier Science, 1986: 1319-1321. [Google Scholar]
- Reisberg B, Ferris SH, Franssen E: An ordinal functional assessment tool for Alzheimer's-type dementia. Hospital & Community Psychiatry. 1985; 36: 593-595. [DOI] [PubMed] [Google Scholar]
- Reisberg B: Dementia: A systematic approach to identifying reversible causes. Geriatrics. 1986; 41(4): 30-46. [PubMed] [Google Scholar]
- Folstein MF, Folstein SE, McHugh PR: Mini-mental state: A practical method for grading the cognitive state of patients for the clinician. J Psychiatric Research. 1975; 12: 189-198. [DOI] [PubMed] [Google Scholar]
- Auer SR, Sclan SG, Yaffee RA, Reisberg B: The neglected half of Alzheimer disease: Cognitive and functional concomitants of severe dementia. J American Geriatrics Society. 1994; 42:1266-1272. [DOI] [PubMed] [Google Scholar]
- Bobinski M, Wegiel J, Wisniewski HM, et al.: Atrophy of hippocampal formation subdivisions correlates with stage and duration of Alzheimer disease. Dementia. 1995; 6: 205-210. [DOI] [PubMed] [Google Scholar]
- Bobinski M, Wegiel J, Tarnawski M, et al.: Relationships between regional neuronal loss and neurofibrillary changes in the hippocampal formation and duration and severity of Alzheimer disease. J Neuropathology & Experimental Neurology. 1997; 56: 414-420. [DOI] [PubMed] [Google Scholar]
- Reisberg B, Ferris SH, Franssen E, et al.: Mortality and temporal course of probable Alzheimer's disease: A five-year prospective study. International Psychogeriatrics. 1996; 8: 291-311. [DOI] [PubMed] [Google Scholar]
- Reisberg B, Schneck MK, Ferris SH, et al.: The brief cognitive rating scale (BCRS): Findings in primary degenerative dementia (PDD). Psychopharmacology Bulletin. 1983; 19: 47-50. [Google Scholar]
- Reisberg B, Ferris SH, deLeon MJ, Crook T: The global deterioration scale for assessment of primary degenerative dementia. American J Psychiatry. 1982; 139: 1136-1139. [DOI] [PubMed] [Google Scholar]
- Reisberg B, Ferris SH, de Leon MJ: Senile dementia of the Alzheimer type: Diagnostic and differential diagnostic features with special reference to functional assessment staging. In Traber J, Gispen WH (eds.): Senile Dementia of the Alzheimer Type (Vol. 2). Berlin: Springer-Verlag, 1985: 18-37. [Google Scholar]
- Reisberg B, Pattschull-Furlan A, Franssen E, et al.: Cognitionrelated functional, praxis and feeding changes in CNS aging and Alzheimer's disease and their developmental analogies. In Beyreuther KG, Schettler G (eds.): Molecular Mechanisms of Aging. Berlin: Springer-Verlag, 1990: 18-40. [Google Scholar]
- Ouvrier RA, Goldsmith RF, Ouvrier S, Williams IC: The value of the mini-mental state examination in childhood: A preliminary study. J Child Neurology. 1993; 8: 145-148. [DOI] [PubMed] [Google Scholar]
- Sclan SG, Foster JR, Reisberg B, et al.: Application of Piagetian measures of cognition in severe Alzheimer's disease. Psychiatric J University of Ottawa. 1990; 15: 221-226. [PubMed] [Google Scholar]
- Thornbury MM: Cognitive performance on Piagetian tasks by Alzheimer's disease patients. Research in Nursing & Health. 1992; 15: 11-18. [DOI] [PubMed] [Google Scholar]
- Reisberg B, Ferris S: A clinical rating scale for symptoms of psychosis in Alzheimer's disease. Psychopharmacology Bulletin. 1985; 21: 101-104. [PubMed] [Google Scholar]
- Reisberg B, Borenstein J, Salob SP, et al.: Behavioral symptoms in Alzheimer's disease: Phenomenology and treatment. J Clinical Psychiatry. 1987; 48 (Suppl): 9-15. [PubMed] [Google Scholar]
- Reisberg B, Franssen E, Sclan SG, et al.: Stage specific incidence of potentially remediable behavioral symptoms in aging and Alzheimer's disease: A study of 120 patients using the BEHAVEAD. Bulletin of Clinical Neurosciences. 1989; 54: 95-112. [Google Scholar]
- Reisberg B, Auer SR, Monteiro I, et al.: A rational psychological approach to the treatment of behavioral disturbances and symptomatology in Alzheimer's disease based upon recognition of the developmental age. International Academy for Biomedical and Drug Research. 1998; 13: 102-109. [Google Scholar]
- Reisberg B, Kenowsky S, Franssen EH, et al.: President's Report: Towards a science of Alzheimer's disease management: A model based upon current knowledge of retrogenesis. International Psychogeriatrics. 1999; 11: 7-23. [DOI] [PubMed] [Google Scholar]
- Paulson G, Gottlieb G: Developmental reflexes: The reappearance of foetal and neonatal reflexes in aged patients. Brain. 1968; 91: 37-52.5643282 [Google Scholar]
- Jacobs L, Gossman MD: Three primitive reflexes in normal adults. Neurology. 1980; 30: 184-188. [DOI] [PubMed] [Google Scholar]
- Basavaraju NG, Silberstone F, Libow L, Paraskeros K: Primitive reflexes and perceptual sensory tests in the elderly—their usefulness in dementia. J Chronic Disease. 1981; 34: 367-377. [DOI] [PubMed] [Google Scholar]
- Huff FJ, Boller F, Luchelli F, et al.: The neurologic examination in patient's with probable Alzheimer's disease. Archives of Neurology. 1987; 44: 929-932. [DOI] [PubMed] [Google Scholar]
- Franssen EH, Reisberg B, Kluger A, et al.: Cognition independent neurologic symptoms in normal aging and probable Alzheimer's disease. Archives of Neurology. 1991; 48: 148-154. [DOI] [PubMed] [Google Scholar]
- Franssen EH, Souren LEM, Torossian CL, Reisberg B: The neurologic syndrome of severe Alzheimer's disease: Relationship to functional decline. Archives of Neurology. 1993; 50: 1029-1039. [DOI] [PubMed] [Google Scholar]
- Franssen EH, Souren LEM, Torossian CL, Reisberg B: Utility of developmental reflexes in the differential diagnosis and prognosis of incontinence in Alzheimer's disease. J Geriatric Psychiatry & Neurology. 1997; 10: 22-28. [DOI] [PubMed] [Google Scholar]
- Brun A, Gustafson L: Distribution of cerebral degeneration in Alzheimer's disease. Archiv fur Psychiatrie und Nervenkrankheiten. 1976; 223: 15-33. [DOI] [PubMed] [Google Scholar]
- McGeer PL, McGeer EG, Akiyama H, et al.: Neuronal degeneration and memory loss in Alzheimer's disease and aging. Experimental Brain Research. 1990; (Supp. 21): 411-426. [Google Scholar]
- Braak H, Braak E: Development of Alzheimer-related neurofibrillary changes in the neocortex inversely recapitulates cortical myelogenesis. Acta Neuropathologica. 1996; 92: 197-201. [DOI] [PubMed] [Google Scholar]
- Raz N: Aging of the brain and its impacts on cognitive performance: Integration of structural and functional findings. In Craik FIM, Salthouse TA (eds.): Handbook of Aging & Cognition—II. Mahwah, NJ: Erlbaum, 2000: 1-90. [Google Scholar]
- Wu Q, Combs C, Cannady SB, Geldmacher DS, Herrup K: Betaamyloid activated microglia induce cell cycling and cell death in cultured cortical neurons. Neurobiology of Aging. 2000; 21: 797-806. [DOI] [PubMed] [Google Scholar]
- Lee M-S, Kwon YT, Li M, et al.: Neurotoxicity induces cleavage of p35 to p25 by calpain. Nature. 2000; 405: 360-364. [DOI] [PubMed] [Google Scholar]
- Patrick GN, Zukerberg L, Nikolic M, et al.: Conversion of p35 to p25 deregulates Cdk5 activity and promotes neurodegeneration. Nature. 1999; 402: 615-622. [DOI] [PubMed] [Google Scholar]
- Nagy Z, Esiri MM, Smith AD: The cell division cycle and the pathophysiology of Alzheimer's disease. Neuroscience. 1998; 87: 731-739. [DOI] [PubMed] [Google Scholar]
- Nagy Z: Cell cycle regulatory failure in neurones causes and consequences. Neurobiology of Aging. 2000; 21: 761-769. [DOI] [PubMed] [Google Scholar]
- Busser J, Geldmacher DS, Herrup K: Ectopic cell cycle proteins predict the sites of neuronal cell death in Alzheimer's disease brain. J Neuroscience. 1998; 18: 2801-2807. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Arendt T, Holzer M, Stöbe A, et al.: Activated mitogenic signaling induces a process of dedifferentiation in Alzheimer's disease that eventually results in cell death. Annals of the New York Academy of Sciences. 2000; 920: 249-255. [DOI] [PubMed] [Google Scholar]
- Arendt T: Alzheimer's disease as a loss of differentiation control in a subset of neurons that retain immature features in the adult brain. Neurobiology of Aging. 2000; 21: 783-796. [DOI] [PubMed] [Google Scholar]
- Arendt T: Alzheimer's disease as a disorder of mechanisms underlying structural brain self-organization. Neuroscience. 2001; 102: 723-765. [DOI] [PubMed] [Google Scholar]
- Smith MZ, Nagy Z, Esiri MM: Cell cycle-related protein expression in vascular dementia and Alzheimer's disease. Neuroscience Letters. 1999; 271: 45-48. [DOI] [PubMed] [Google Scholar]
- Vincent I, Jicha G, Rosado M, Dickson DW: Aberrant expression of mitogenic Cdc2/cyclin B1 kinase in degenerating neurons of Alzheimer's disease brain. J Neuroscience. 1997; 17: 3588-3598. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Vincent I: Cycling to the finish. Neurobiology of Aging. 2000; 21: 757-760. [DOI] [PubMed] [Google Scholar]
- Husseman, JW, Nochlin D, Vincent I: Mitotic activation: A convergent mechanism for a cohort of neurodegenerative diseases. Neurobiology of Aging. 2000; 21: 815-828. [DOI] [PubMed] [Google Scholar]
- Atkins CM, Selcher JC, Petraitis JJ, et al.: The MAPK cascade is required for mammalian associative learning. Nature Neuroscience. 1998; 1: 602-609. [DOI] [PubMed] [Google Scholar]
- Blum S, Moore AN, Adams F, Dash PK: A mitogen-activated protein kinase cascade in the CA1/CA2 subfield of the dorsal hippocampus is essential for long-term spatial memory. J Neuroscience. 1999; 19: 3535-3544. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Schafe GE, Nadel NV, Sullivan GM, et al.: Memory consolidation for contextual and auditory fear conditioning is dependent on protein synthesis, PKA, and MAP kinase. Learning & Memory. 1999; 6: 97-110. [PMC free article] [PubMed] [Google Scholar]
- Selcher JC, Atkins CM, Trzaskos JM, et al.: A necessity for MAP kinase activation in mammalian spatial learning. Learning & Memory. 1999; 6: 478-490. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Kobayashi S, Ishiguro K, Omori A, et al.: A cdc2-related kinase PSSALRE/cdk5 is homologous with the 30kDa subunit of tau protein kinase II, a proline-directed protein kinase associated with microtubule. Federation of European Biochemical Societies Letters. 1993; 335: 171-175. [DOI] [PubMed] [Google Scholar]
- Ledesma MD, Correas I, Avila J, Diaznido J: Implication of brain Cdc2 and Map2 kinases in the phosphorylation of tau protein in Alzheimer's-disease. Federation of European Biochemical Societies Letters. 1992; 308: 218-224. [DOI] [PubMed] [Google Scholar]
- Suzuki T, Oishi M, Marshak DR, et al.: Cell cycle-dependent regulation of the phosphorylation and metabolism of the Alzheimer amyloid precursor protein. EMBO J. 1994; 13: 1114-1122. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Clark R, Smith D, Jobst KA, et al.: Folate, vitamin B12, and serum total homocysteine levels in confirmed Alzheimer disease. Archives of Neurology. 1998; 55: 1449-1455. [DOI] [PubMed] [Google Scholar]
- Kristensen MO, Gulmann NC, Christensen JEJ, et al.: Serum cobalamin and methylmalonic acid in Alzheimer dementia. Acta Neurologica Scandinavica. 1993; 87: 475-481. [DOI] [PubMed] [Google Scholar]
- Diaz-Arrastia R: Hyperhomocysteinemia: A new risk factor for Alzheimer disease? [Editorial]. Archives of Neurology. 1998; 55: 1407-1408. [DOI] [PubMed] [Google Scholar]
- Hofman A, Ott A, Breteler MMB, et al.: Atherosclerosis, apolipoprotein E, and prevalence of dementia and Alzheimer's disease in the Rotterdam Study. Lancet. 1997; 349: 151-154. [DOI] [PubMed] [Google Scholar]
- Snowdon DA, Greiner LH, Mortimer JA, et al.: Brain infarction and the clinical expression of Alzheimer's disease: The nun study. JAMA. 1997; 277: 813-817. [PubMed] [Google Scholar]
- Esiri MM, Nagy Z, Smith MZ, et al.: Cerebrovascular disease and threshold for dementia in the early stages of Alzheimer's disease. Lancet. 1999; 354: 919-920. [DOI] [PubMed] [Google Scholar]
- Reisberg B, Franssen E, Shah MA, et al.: Clinical diagnosis of dementia. In Maj M, Sartorius N (eds.): World Psychiatric Association Series. Evidence & Experience in Psychiatry: Dementia (Vol. 3). Chichester, UK: John Wiley and Sons, 2000: 69-115. [Google Scholar]
- Souren LEM, Franssen EM, Reisberg B: Contractures and loss of function in patients with Alzheimer's disease. J American Geriatrics Society. 1995; 43: 650-655. [DOI] [PubMed] [Google Scholar]
- Blessed G, Tomlinson BE, Roth M: The association between quantitative measures of dementia and senile change in the cerebral gray matter of elderly subjects. British J Psychiatry. 1968; 114: 797-811. [DOI] [PubMed] [Google Scholar]
- Souren LEM, Franssen EH, Reisberg B: Neuromotor changes in Alzheimer's disease: Implications for patient care. J Geriatric Psychiatry & Neurology. 1997; 10: 93-98. [DOI] [PubMed] [Google Scholar]
- Raina AK, Zhu X, Rottkamp CA, et al.: Cyclin’ toward dementia: Cell cycle abnormalities and abortive oncogenesis in Alzheimer disease. J Neuroscience Research. 2000; 61: 128-133. [DOI] [PubMed] [Google Scholar]
- Zhu X, Raina AK, Boux H, et al.: Activation of oncogenic pathways in degenerating neurons in Alzheimer disease. International J Developmental Neuroscience. 2000; 18: 433-437. [DOI] [PubMed] [Google Scholar]
- Raina AK, Zhu X, Monteiro M, et al.: Abortive oncogeny and cell cycle-mediated events in Alzheimer disease. In Meijer L, Jezequel A, Ducommun B (eds.): Progress in Cell Cycle Research. New York: Kluwer Academic/Plenum Publishers, 2000: 235-242. [DOI] [PubMed] [Google Scholar]