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Non-cognitive symptoms and related conditions in the Alzheimer’s disease: a literature review

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Abstract

The Alzheimer’s disease is considered a progressive cognitive disorder; however, several non-cognitive symptoms accompany all stages of the disease, appearing at times before the cognitive symptoms become manifest. This article reviews the literature on non-cognitive symptoms normally related to the Alzheimer’s disease, including gait and balance dysfunction, olfactory dysfunction, diabetes, pain, and psychiatric symptoms.

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References

  1. McKhann G, Drachman D, Folstein M, Katzman R, Price D, Stadlan EM (1984) Clinical diagnosis of Alzheimer’s disease: report of the NINCDS-ADRDA Work Group under the auspices of Department of Health and Human Services Task Force on Alzheimer’s Disease. Neurology 34:939–944

    Article  PubMed  CAS  Google Scholar 

  2. Alzheimer A (1907) Uber eine eigenartige Erkrankung der Hirnrinde. Allg Zeitschr Psychiatr 64:146–148

    Google Scholar 

  3. Braak H, Braak E (1995) Staging of Alzheimer’s disease-related neurofibrillary changes. Neurobiol Aging 16:271–284

    Article  PubMed  CAS  Google Scholar 

  4. Braak H, Thalam DR, Ghebremedhin E, Del Tredici K (2011) Stages of the pathologic process in Alzheimer disease: age categories from 1 to 100 years. J Neuropathol Exp Neurol 70:960–969

    Article  PubMed  CAS  Google Scholar 

  5. Saito Y, Murayama S (2000) Expression of tau immunoreactivity in the spinal motor neurons of Alzheimer’s disease. Neurology 55:1727–1729

    Article  PubMed  CAS  Google Scholar 

  6. Schmidt ML, Zhukareva V, Perl DP, Sheridan SK, Schuck T, Lee VMY, Trjanowskj JQ (2001) Spinal cord neurofibrillary pathology in Alzheimer disease and Guam Parkinsonism-dementia complex. J Neuropathol Exp Neurol 60:1075–1086

    PubMed  CAS  Google Scholar 

  7. Miklossy J, Taddei K, Martins R, Escher G, Kraftsik R, Pillevuit O, Lepori D, Campiche M (1999) Alzheimer disease: curly fibers and tangles in organs other than brain. J Neuropathol Exp Neurol 58:803–814

    Article  PubMed  CAS  Google Scholar 

  8. Wirths O, Weis J, Szczygielski J, Multhaup G, Bayer TA (2006) Axonopathy in an APP/PS1 transgenic mouse model of Alzheimer’s disease. Acta Neuropathol 111:312–319

    Article  PubMed  CAS  Google Scholar 

  9. Filali M, Lalonde R, Rivest S (2009) Cognitive and non-cognitive behaviors in an APPswe/PS1 bigenic model of Alzheimer’s disease. Genes Brain Behav 8:143–148

    Article  PubMed  CAS  Google Scholar 

  10. Pugh PL, Richardson JC, Bate ST, Upton N, Sunter D (2007) Non-cognitive behaviours in an APP/PS1 transgenic model of Alzheimer’s disease. Behav Brain Res 178:18–28

    Article  PubMed  CAS  Google Scholar 

  11. Hl Klawans, Tufo HM, Ostfeld AM, Shekelle RB, Kilbridge JA (1971) Neurologic examination in an elderly population. Dis Nerv Syst 32:274–279

    Google Scholar 

  12. Gleason CE, Gangnon RE, Fisher BL, Mahoney JE (2009) Increased risk for falling associated with subtle cognitive impairment: secondary analysis of a randomized clinical trial. Dement Geriatr Cogn Disord 27:557–563

    Article  PubMed  Google Scholar 

  13. Thomas VS, Vandenberg EV, Potter JF (2002) Non-neurological factors are implicated in impairments in gait and mobility among patients in a clinical dementia referral population. Int J Geriatr Psychiatry 17:128–133

    Article  PubMed  Google Scholar 

  14. Van Schoor NM, Smit JH, Pluijm SMF, Jonker C, Lips P (2002) Different cognitive functions in relation to falls among older persons. Immediate memory as an independent risk factor for falls. J Clin Epidemiol 55:855–862

    Article  PubMed  Google Scholar 

  15. Naslund J (2010) Visuospatial ability in relation to fall risk and dementia. Arch Neurol 67:643–644

    Article  PubMed  Google Scholar 

  16. Verghese J, Wang C, Lipton RB, Holtzer R, Xue X (2007) Quantitative gait dysfunction and risk of cognitive decline and dementia. J Neurol Neurosurg Psychiatry 78:929–935

    Article  PubMed  Google Scholar 

  17. Kotagal V, Muller ML, Kaufer DI, Koeppe RA, Bohnen NI (2012) Thalamic cholinergic innervation is spared in Alzheimer disease compared to parkinsonian disorders. Neurosci Lett 514:169–172

    Article  PubMed  CAS  Google Scholar 

  18. Jolivalt CG, Calcutt NA, Masliah E (2012) Similar pattern of peripheral neuropathy in mouse models of type 1 diabetes and Alzheimer’s disease. Neuroscience 202:405–412

    Article  PubMed  CAS  Google Scholar 

  19. Nousiainen U, Partanen J, Koivisto K, Soininen H, Riekkinen PJ (1991) Electroneuromyographic findings in patients with Alzheimer’s disease. Electromyogr Clin Neurophysiol 31:119–122

    PubMed  CAS  Google Scholar 

  20. Waldton S (1974) Clinical observations of impaired cranial nerve function in senile dementia. Acta Psychiatr Scand 50:539–547

    Article  PubMed  CAS  Google Scholar 

  21. Rezek DJ (1987) Olfactory deficits as a neurologic sign in dementia of Alzheimer type. Arch Neurol 44:1030–1103

    Article  PubMed  CAS  Google Scholar 

  22. Berthoud HR (2011) Metabolic and hedonic drives in the neural control of appetite: who is the boss? Curr Opin Neurobiol 21:888–896

    Article  PubMed  CAS  Google Scholar 

  23. Thompson MD, Knee K, Golden CJ (1998) Olfaction in persons with Alzheimer’s disease. Neuropsychol Review 8:11–23

    Article  CAS  Google Scholar 

  24. Mesholam RI, Moberg PJ, Mahr RN, Doty RL (1998) Olfaction in neurodegenerative disease. A meta-analysis of olfactory functioning in Alzheimer’s and Parkinson’s diseases. Arch Neurol 55:84–90

    Article  PubMed  CAS  Google Scholar 

  25. Devanand DP, Liu X, Tabert MH, Pradhaban G, Cuasay K, Bell K, de Leon MJ, Doty RL, Stern Y, Pelton GH (2008) Combining early markers strongly predicts conversion from mild cognitive impairment to Alzheimer’s disease. Biol Psychiatry 64:871–879

    Article  PubMed  Google Scholar 

  26. Forster S, Vaitl A, Teipel SJ, Yakushev I, Mustafa M, la Fougere C, Rominger A, Cumming P, Bartenstein P, Hampel H, Hummel T, Buerger K, Hundt W, Steinbach S (2010) Functional representation of olfactory impairment in early Alzheimer’s disease. J Alzheimers Dis 22:581–591

    PubMed  Google Scholar 

  27. Wilson RS, Arnold SE, Schneider JA, Tang Y, Bennet DA (2007) The relationship between cerebral Alzheimer’s disease pathology and odour identification in old age. J Neurol Neurosurg Psychiatry 78:30–35

    Article  PubMed  CAS  Google Scholar 

  28. Bahar-Fuchs A, Chetelat G, Villemagne VL, Moss S, Pike K, Mastes CL, Rowe C, Savage G (2000) Olfactory deficits and amyloid-β burden in Alzheimer’s disease, mild cognitive impairment, and healthy aging: a PiB PET study. J Alzheimers Dis 22:1081–1087

    Google Scholar 

  29. Li W, Howard JD, Gottfried JA (2010) Disruption of odour quality coding in piriform cortex mediates olfactory deficits in Alzheimer’s disease. Brain 133:2714–2726

    Article  PubMed  Google Scholar 

  30. Wesson DW, Borkowski AH, Landreth GE, Nixon RA, Levy E, Wilson DA (2011) Sensory network dysfunction, behavioral impairments, and their reversibility in an Alzheimer’s β-amyloidosis mouse model. J Neurosci 31:15962–15971

    Article  PubMed  CAS  Google Scholar 

  31. Murphy C, Bacon AW, Bondi MW, Salmon DP (1998) Apolipoprotein E status is associated with odor identification deficits in nondemented older persons. Ann NY Acad Sci 855:744–750

    Article  PubMed  CAS  Google Scholar 

  32. Pickering G, Jourdan D, Dubray C (2005) Acute versus chronic pain treatment in Alzheimer’s disease. Eur J Pain 10:379–384

    Article  PubMed  Google Scholar 

  33. Pickering G, Eschalier A, Dubray C (2000) Pain and Alzheimer’s disease. Gerontology 46:235–241

    Article  PubMed  CAS  Google Scholar 

  34. Benedetti F, Arduino C, Costa S, Vighetti S, Tarenzi L, Rainero I, Asteggiano G (2006) Loss of expectation-related mechanisms in Alzheimer’s disease makes analgesic therapies less effective. Pain 121:133–144

    Article  PubMed  CAS  Google Scholar 

  35. Cole LJ, Gravilescu M, Johnston LA, Gibson SJ, Farrell MJ, Egan GF (2011) The impact of Alzheimer’s disease on the functional connectivity between brain regions underlying pain perception. Eur J Pain 15:568e1–568e11

    Google Scholar 

  36. Monastero R, Mangialasche R, Camarda C, Ercolani S, Camarda SA (2009) A systematc review of neuropsychiatric symptoms in mild cognitive impairment. J Alzheimers Dis 18:11–30

    PubMed  Google Scholar 

  37. Gonfrier S, Andrieu S, Renaud D, Vellas B, Robert PH (2012) Course of neuropsychiatric symptoms during a 4-years follow up in the REAL-FR cohort. J Nutr Health Aging 16:134–137

    Article  PubMed  CAS  Google Scholar 

  38. Rozzini L, Vicini Chilovi B, Conti M, Delro I, Borrono B, Trabucchi M, Padovani A (2008) Neuropsychiatric symptoms in amnestic and nonamnestic mild cognitive impairment. Dement Geriatr Cogn Disord 25:32–36

    Article  PubMed  CAS  Google Scholar 

  39. Ownby RL, Crocco E, Acevedo A, John V, Lowenstein D (2006) Depression and risk for Alzheimer’s disease: systematic review, meta-analysis, and metaregression analysis. Arch Gen Psychiatry 63:530–538

    Article  PubMed  Google Scholar 

  40. Byers AL, Yaffe K (2011) Depression and risk of developing dementia. Nat Rev Neurol 7:323–331

    Article  PubMed  CAS  Google Scholar 

  41. Royall DR, Palmer R, Chiodo LK, Polk MJ (2012) Depressive symptoms predict longitudinal change in executive control but not memory. Int J Geriatr Psychiatry 27:89–96

    Article  PubMed  Google Scholar 

  42. Palmer K, Di Iulio F, Varsi AE, Gianni W, Sancesario G, Caltagirone C, Spalletta G (2010) Neuropsychiatric predictors of progression from amnestic-mild cognitive impairment to Alzheimer’s disease: the role of depression and apathy. J Alzheimers Dis 20:175–183

    PubMed  Google Scholar 

  43. Fernandez-Martinez M, Molano A, Castro J, Zarranz JJ (2010) Prevalence of neuropsychiatric simptoms in mild cognitive impairment and Alzheimer’s disease, and its relationship with cognitive impairment. Curr Alzheimer Res 7:517–526

    Article  CAS  Google Scholar 

  44. Tsopelas C, Stewart R, Savva GM, Brayne C, Ince P, Thomas A, Matthews FE (2011) Medical research council cognitive function and ageing study. Neuropathological correlates of late-life depression in older people. Br J Psychiatry 198:104–109

    Article  Google Scholar 

  45. Rubio A, Vestner AL, Stewart JM, Forbes NT, Conwell Y, Cox C (2001) Suicide and Alzheimer’s pathology in the elderly: a case-control study. Biol Psychiatry 49:137–145

    Article  PubMed  CAS  Google Scholar 

  46. Peisah C, Snowdon J, Gorrie C, Kril J, Rodriguez M (2007) Investigation of Alzheimer’s disease-related pathology in community dwelling older subjects who committed suicide. J Affect Disord 99:127–132

    Article  PubMed  CAS  Google Scholar 

  47. Ropacki SA, Jeste DV (2005) Epidemiology of and risk factors for psychosis of Alzheimer’s disease: a review of 55 studies published from 1990 to 2003. Am J Psychiatry 162:2022–2030

    Article  PubMed  Google Scholar 

  48. Leroi I, Voulgari A, Breiner JC, Lyketsos CG (2003) The epidemiology of psychosis in dementia. Am J Geriatr Psychiatry 11:83–91

    PubMed  Google Scholar 

  49. Lyketsos C, Breitner JCS, Rabins PV (2001) An evidence-based proposal for the classification of neuropsychiatric disturbance in Alzheimer’s disease. Int J Geriatr Psychiatry 16:1037–1042

    Article  PubMed  CAS  Google Scholar 

  50. Aalten P, Verhey FR, Boziki M, Bullock R, Byrne EJ, Camus V, Caputo M, Collins D, De Deyn PP, Elina K, Frisoni G, Girtler N, Holmes C, Hurt C, Marriott A, Mecocci P, Nobili F, Ousset PJ, Reynish E, Salmon E, Tsolaki M, Vellas B, Robert PH (2007) Neuropsychiatric syndromes in dementia. Results from the European Alzheimer Disease Consortium: part I. Dement Geriatr Cogn Disord 24:457–463

    Article  PubMed  Google Scholar 

  51. Taragano FE, Allegri RF, Krupitzki H, Sarasola D, Serrano CM, Lon L, Lyketsos CG (2009) Mild behavioral impairment and risk of dementia. J Clin Psychiatry 70:584–592

    Article  PubMed  Google Scholar 

  52. Pietropaolo S, Delage P, Lebtreton F, Crusio WE, Cho YH (2010) Early development of social deficits in APP and APP-PS1 mice. Neurobiol Aging 33:1002e17–1003e27

    Google Scholar 

  53. Archin S, Mahendra N (2001) Insight in Alzheimer’s patients: results of a longitudinal study using three assessment methods. Am J Alzheimers Dis Other Dem 16:211–224

    Article  Google Scholar 

  54. Kobayashi T, Kato S (2011) Depression-dementia medius: between depression and the manifestation of dementia symptoms. Psychogeriatrics 11:177–182

    Article  PubMed  Google Scholar 

  55. Wuwongse S, Chang RCC, Law ACK (2010) The putative neurodegenerative links between depression and Alzheimer’s disease. Progress Neurobiol 91:362–375

    Article  CAS  Google Scholar 

  56. Kang JY, Lee JS, Kang H, Lee HW, Kim YK, Jeon HJ, Chung JK, Lee MC, Cho MJ, Lee DS (2012) Regional cerebral blood flow abnormalities associated with apathy and depression in Alzheimer disease. Alzheimer Dis Assoc Disord 26:217–224

    Article  PubMed  Google Scholar 

  57. Kramberger MG, Jelic V, Kareholt I, Enache D, Jonhagen ME, Winblad B, Aarsland D (2012) Cerebrospinal fluid Alzheimer markers in depressed elderly subjects with and without Alzheimer’s disease. Dement Geriatr Cogn Disord Extra 2:48–56

    Article  Google Scholar 

  58. Cheng G, Huang C, Wang H (2012) Diabetes as a risk factor for dementia and mild cognitive impairment: a meta-analysis of longitudinal studies. Int Med J 42:489–491

    Article  Google Scholar 

  59. Messier C (2003) Diabetes, Alzheimer’s disease and apolipoprotein genotype. Exp Gerontol 38:941–946

    Article  PubMed  CAS  Google Scholar 

  60. Craft S, Asthana S, Newcomer JW, Wilkinson CV, Matos IT, Baker LD, Cherrier M, Lofgreen C, Latendresse S, Petrova A, Plymate S, Raskind M, Grimwood K, Veit RC (1999) Enhancement of memory in Alzheimer disease with insulin and somatostatin, but not glucose. Arch Gen Psychiatry 56:1135–1140

    Article  PubMed  CAS  Google Scholar 

  61. Marks DR, Tucker K, Cavallin MA, Mast TG, Fadool DA (2009) Awake intranasal insulin delivery modifies protein complexes and alters memory, anxiety, and olfactory behaviors. J Neurosci 29:6734–6751

    Article  PubMed  CAS  Google Scholar 

  62. Alafuzoff I, Aho L, Helisalmi S, Mannermaat A, Soininen H (2009) β-amyloid deposition in brains of subjects with diabetes. Neuropathol Appl Neurobiol 35:60–68

    Article  PubMed  CAS  Google Scholar 

  63. Miklossy J, Quing H, Radenovic A, Kis A, Vileno B, Laszlo F, Miller L, Martins RN, Waeber G, Mooser V, Bosman F, Khalili K, Darbinian N, McGeer PL (2010) Beta amyloid and hyperphosphorilated tau deposits in the pancreas in type 2 diabetes. Neurobiol Aging 31:1503–1515

    Article  PubMed  CAS  Google Scholar 

  64. Burdo JR, Chen Q, Calcutt NA, Schubert D (2009) The pathological interaction between diabetes and presymptomatic Alzheimer’s disease. Neurobiol Aging 30:1910–1917

    Article  PubMed  CAS  Google Scholar 

  65. Takeda S, Sato N, Uchio-Yamada K, Sawada K, Kunieda T, Takeuchi D, Kurinami H, Shinohara M, Rakugi H, Morishita R (2010) Diabetes-accelerated memory dysfunction via cerebrovascular inflammation and Aβ deposition in an Alzheimer mouse model with diabetes. PNAS 107:7036–7041

    Article  PubMed  CAS  Google Scholar 

  66. Steen E, Terry BM, Rivera EJ, Cannon JL, Neely TR, Tavares R, Xu XJ, Wands JR, de la Monte SM (2005) Impaired insulin and insulin-like growth factor expression and signaling mechanisms in Alzheimer’s disease- is this type 3 diabets? J Alzheimers Dis 7:63–80

    PubMed  CAS  Google Scholar 

  67. Talbot K, Wang HY, Kazi H, Han LY, Bakshi KP, Stucki A, Fuino RL, Kawaguchi KR, Samoyedny AJ, Wilson RS, Arvanitakis Z, Schneider JA, Wolf BA, Bennet DA, Trojanowski JQ, Arnold SE (2012) Demonstrated brain insulin resistance in Alzheimer’s disease patients is associated with IGF-1 resistance, IRS-1 dysregulation, and cognitive decline. J Clin Invest 122:1316–1338

    Article  PubMed  CAS  Google Scholar 

  68. Bomfim TR, Forny-Germano L, Sathler LB, Brito-Moreira J, Houzel JC, Decker H, Silverman MA, Kazi H, Melo HM, McClean PL, Holscher C, Arnold SE, Talbot K, Klein WL, Munoz DP, Ferreira ST, De Felice FG (2012) An anti-diabetes agent protects the mouse brain from defective insulin signaling caused by Alzheimer’s disease-associated Aβ oligomers. J Clin Invest 122:1339–1353

    Article  PubMed  CAS  Google Scholar 

  69. Smith MA, Petot GJ, Perry G (1999) Diet and oxidative stress: a novel synthesis of epidemiological data on Alzheimer’s disease. J Alzheimers Dis 1:203–206

    PubMed  CAS  Google Scholar 

  70. Ewald CY, Raps DA, Li C (2012) APL-1, the Alzheimer’s amyloid precursor protein in Caenorhabditis elegans, modulates multiple metabolic pathways throughout development. Genetics 191:493–507

    Article  PubMed  Google Scholar 

  71. Sperling RA, Aisen PS, Beckett AL, Bennet DA, Craft S, Fagan AM, Iwatsubo T, Jack CR, Kaye J, Montine TJ, Park DC, Reiman EM, Rowe CC, Siemers E, Stern Y, Yaffe K, Carillo MC, Thies B, Morrison-Bogorad M, Wagster MV, Phelps CH (2011) Toward defining the preclinical stages of Alzheimer’s disease: recommendations from the National Institute of Aging-Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer’s disease. Alzheimers Dement 7:280–292

    Article  PubMed  Google Scholar 

  72. Langston JW (2006) The Parkinson’s complex: parkinsonism is just the tip of the iceberg. Ann Neurol 59:591–596

    Article  PubMed  Google Scholar 

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  1. Department of Neurology Valduce Hospital, Como, Italy

    Francesco Raudino

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Raudino, F. Non-cognitive symptoms and related conditions in the Alzheimer’s disease: a literature review. Neurol Sci 34, 1275–1282 (2013). https://doi.org/10.1007/s10072-013-1424-7

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