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Cognitive Enhancers as a Means to Reduce Falls in Older Adults

  • Nicolaas I. BohnenEmail author
  • Martijn L. T. M. Müller
Chapter

Abstract

The etiology of falls is multifactorial and hence a single treatment intervention is unlikely to be effective for falling. Cognitive enhancer pharmacotherapy may be of potential benefit to reduce fall risk in older adults with evidence of cognitive impairment. Data from subjects with Parkinson disease (PD) indicate significant reductions in falls with cholinergic augmentation therapy, especially in those with more frequent falls. Preliminary data from cholinesterase inhibitor treatment in patients with mild cognitive impairment (MCI) and Alzheimer disease (AD) suggest that these drugs may improve gait indices that typically reflect higher fall risk. Data from noradrenergic drug clinical trials and gait are less consistent but suggest improved gait functions but only in advanced post-surgical PD subjects. Fall-reducing effects of droxidopa in PD are likely related to the drug’s blood pressure increasing rather than cognitive enhancer effects. Given the accumulating evidence of increased fall risk due to anticholinergic medication burden in non-PD elderly, reduction and preferably elimination of such medications should be a first management step in this population. There is a clear need for cognitive enhancer clinical trials in targeted non-PD elderly at risk of falling. Although fall frequency may be the gold outcome variable for such studies, surrogate measures that reflect increased fall risk may be needed if fall frequency is less than a weekly or monthly occurrence.

Keywords

Acetylcholine Alzheimer disease Brain network Cognition Falls Dementia with Lewy bodies Parkinson disease 

Abbreviations

AD

Alzheimer disease

MCI

mild cognitive impairment

PD

Parkinson disease

PDD

Parkinson disease with dementia

PPN

pedunculopontine nucleus

Notes

Acknowledgment

The presented research data from the authors’ work was supported by grants from the NIH [P01 NS015655, RO1 NS070856, with additional support from P50 NS091856], Department of Veterans Affairs [I01 RX000317] and the Michael J. Fox Foundation.

Human Rights

All reported studies/experiments with human subjects performed by the authors have been previously published and complied with all applicable ethical standards (including the Helsinki declaration and its amendments, institutional/national research committee standards, and international/national/institutional guidelines).

Disclosure

No potential conflicts of interest relevant to this chapter were reported.

References

  1. 1.
    Aizenberg D, Sigler M, Weizman A, Barak Y. Anticholinergic burden and the risk of falls among elderly psychiatric inpatients: a 4-year case-control study. Int Psychogeriatr. 2002;14:307–10.CrossRefGoogle Scholar
  2. 2.
    Allan LM, Ballard CG, Rowan EN, Kenny RA. Incidence and prediction of falls in dementia: a prospective study in older people. PLoS One. 2009;4:e5521.  https://doi.org/10.1371/journal.pone.0005521.CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    Allen NE, Schwarzel AK, Canning CG. Recurrent falls in Parkinson's disease: a systematic review. Parkinsons Dis. 2013;2013:906274.  https://doi.org/10.1155/2013/906274.CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    Anand V, Buckley JG, Scally A, Elliott DB. Postural stability in the elderly during sensory perturbations and dual tasking: the influence of refractive blur. Invest Ophthalmol Vis Sci. 2003;44:2885–91.CrossRefGoogle Scholar
  5. 5.
    Ancelin ML, Artero S, Portet F, Dupuy AM, Touchon J, Ritchie K. Non-degenerative mild cognitive impairment in elderly people and use of anticholinergic drugs: longitudinal cohort study. BMJ. 2006;332:455–9.  https://doi.org/10.1136/bmj.38740.439664.DE.CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Assal F, Allali G, Kressig RW, Herrmann FR, Beauchet O. Galantamine improves gait performance in patients with Alzheimer’s disease. J Am Geriatr Soc. 2008;56:946–7. doi:JGS1657 [pii].  https://doi.org/10.1111/j.1532-5415.2008.01657.x.CrossRefGoogle Scholar
  7. 7.
    Atri A, et al. Effect of idalopirdine as adjunct to cholinesterase inhibitors on change in cognition in patients with Alzheimer disease: three randomized clinical trials. JAMA. 2018;319:130–42.  https://doi.org/10.1001/jama.2017.20373.CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Auriel E, Hausdorff JM, Giladi N. Methylphenidate for the treatment of Parkinson disease and other neurological disorders. Clin Neuropharmacol. 2009;32:75–81.  https://doi.org/10.1097/WNF.0B013E318170576C.. 00002826-200903000-00004 [pii]CrossRefPubMedGoogle Scholar
  9. 9.
    Auriel E, Hausdorff JM, Herman T, Simon ES, Giladi N. Effects of methylphenidate on cognitive function and gait in patients with Parkinson’s disease: a pilot study. Clin Neuropharmacol. 2006;29:15–7.CrossRefGoogle Scholar
  10. 10.
    Beauchet O, Launay CP, Montero-Odasso M, Annweiler C, Allali G. Anti-dementia drugs-related changes in gait performance while single and dual tasking in patients with Alzheimer disease: a meta-analysis. Curr Alzheimer Res. 2015;12:761–71.CrossRefGoogle Scholar
  11. 11.
    Beaulieu ML, Muller M, Bohnen NI. Have we been overestimating fall rates in Parkinson’s disease? Mov Disord. 2017;32:803.  https://doi.org/10.1002/mds.26994.CrossRefPubMedGoogle Scholar
  12. 12.
    Bernheimer H, Birkmayer W, Hornykiewicz O, Jellinger K, Seitelberger F. Brain dopamine and the syndromes of Parkinson and Huntington. Clinical, morphological and neurochemical correlations. J Neurol Sci. 1973;20:415–55.CrossRefGoogle Scholar
  13. 13.
    Bohnen NI, Albin RL, Koeppe RA, Wernette KA, Kilbourn MR, Minoshima S, Frey KA. Positron emission tomography of monoaminergic vesicular binding in aging and Parkinson disease. J Cereb Blood Flow Metab. 2006;26:1198–212.CrossRefGoogle Scholar
  14. 14.
    Bohnen NI, et al. Cortical cholinergic function is more severely affected in parkinsonian dementia than in Alzheimer disease: an in vivo positron emission tomographic study. Arch Neurol. 2003;60:1745–8.  https://doi.org/10.1001/archneur.60.12.1745.CrossRefPubMedGoogle Scholar
  15. 15.
    Bohnen NI, Muller ML, Koeppe RA, Studenski SA, Kilbourn MA, Frey KA, Albin RL. History of falls in Parkinson disease is associated with reduced cholinergic activity. Neurology. 2009a;73:1670–6. doi:73/20/1670 [pii].  https://doi.org/10.1212/WNL.0b013e3181c1ded6.CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Bohnen NI, Muller ML, Kuwabara H, Cham R, Constantine GM, Studenski SA. Age-associated striatal dopaminergic denervation and falls in community-dwelling subjects. J Rehabil Res Dev. 2009b;46:1045–52.CrossRefGoogle Scholar
  17. 17.
    Bohnen NI, et al. Heterogeneity of cholinergic denervation in Parkinson’s disease without dementia. J Cereb Blood Flow Metab. 2012;32:1609–17.  https://doi.org/10.1038/jcbfm.2012.60.CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Cao YJ, et al. Physical and cognitive performance and burden of anticholinergics, sedatives, and ACE inhibitors in older women. Clin Pharmacol Ther. 2008;83:422–9.  https://doi.org/10.1038/sj.clpt.6100303.CrossRefPubMedGoogle Scholar
  19. 19.
    Chung KA, Lobb BM, Nutt JG, Horak F. Cholinergic augmentation in frequently fallings subjects with Parkinson’s disease. Mov Disord. 2009;24(Suppl 1):S259.Google Scholar
  20. 20.
    Chung KA, Lobb BM, Nutt JG, Horak FB. Effects of a central cholinesterase inhibitor on reducing falls in Parkinson disease. Neurology. 2010;75:1263–9. doi:WNL.0b013e3181f6128c [pii].  https://doi.org/10.1212/WNL.0b013e3181f6128c.CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Devos D, et al. Improvement of gait by chronic, high doses of methylphenidate in patients with advanced Parkinson’s disease. J Neurol Neurosurg Psychiatry. 2007;78:470–5.CrossRefGoogle Scholar
  22. 22.
    Dubois B, et al. Donepezil in Parkinson’s disease dementia: a randomized, double-blind efficacy and safety study. Mov Disord. 2012;27:1230–8.  https://doi.org/10.1002/mds.25098.CrossRefPubMedGoogle Scholar
  23. 23.
    Ensrud KE, et al. Central nervous system-active medications and risk for falls in older women. J Am Geriatr Soc. 2002;50:1629–37.CrossRefGoogle Scholar
  24. 24.
    Epstein NU, Guo R, Farlow MR, Singh JP, Fisher M. Medication for Alzheimer’s disease and associated fall hazard: a retrospective cohort study from the Alzheimer’s Disease Neuroimaging Initiative. Drugs Aging. 2014;31:125–9.  https://doi.org/10.1007/s40266-013-0143-3.CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Eriksson S, Gustafson Y, Lundin-Olsson L. Risk factors for falls in people with and without a diagnose of dementia living in residential care facilities: a prospective study. Arch Gerontol Geriatr. 2008;46:293–306.  https://doi.org/10.1016/j.archger.2007.05.002.CrossRefPubMedGoogle Scholar
  26. 26.
    Espay AJ, et al. Methylphenidate for gait impairment in Parkinson disease: a randomized clinical trial. Neurology. 2011;76:1256–62.  https://doi.org/10.1212/WNL.0b013e3182143537.CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Franchignoni F, Horak F, Godi M, Nardone A, Giordano A. Using psychometric techniques to improve the Balance Evaluation Systems Test: the mini-BESTest. J Rehabil Med. 2010;42:323–31.  https://doi.org/10.2340/16501977-0537.CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Godfrey A. Wearables for independent living in older adults: gait and falls. Maturitas. 2017;100:16–26.  https://doi.org/10.1016/j.maturitas.2017.03.317.CrossRefPubMedGoogle Scholar
  29. 29.
    Hasselmo ME, Sarter M. Modes and models of forebrain cholinergic neuromodulation of cognition. Neuropsychopharmacology. 2011;36:52–73. doi:npp2010104 [pii].  https://doi.org/10.1038/npp.2010.104.CrossRefPubMedGoogle Scholar
  30. 30.
    Hausdorff JM, Balash J, Giladi N. Effects of cognitive challenge on gait variability in patients with Parkinson’s disease. J Geriatr Psychiatry Neurol. 2003;16:53–8.CrossRefGoogle Scholar
  31. 31.
    Hausdorff JM, Doniger GM, Springer S, Yogev G, Giladi N, Simon ES. A common cognitive profile in elderly fallers and in patients with Parkinson’s disease: the prominence of impaired executive function and attention. Exp Aging Res. 2006;32:411–29.CrossRefGoogle Scholar
  32. 32.
    Hauser RA, Heritier S, Rowse GJ, Hewitt LA, Isaacson SH. Droxidopa and reduced falls in a trial of Parkinson fdisease patients with neurogenic orthostatic hypotension. Clin Neuropharmacol. 2016;39:220–6.  https://doi.org/10.1097/WNF.0000000000000168.CrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    Henderson EJ, et al. Rivastigmine for gait stability in patients with Parkinson’s disease (ReSPonD): a randomised, double-blind, placebo-controlled, phase 2 trial. Lancet Neurol. 2016;  https://doi.org/10.1016/S1474-4422(15)00389-0.CrossRefGoogle Scholar
  34. 34.
    Herman T, Mirelman A, Giladi N, Schweiger A, Hausdorff JM. Executive control deficits as a prodrome to falls in healthy older adults: a prospective study linking thinking, walking, and falling. J Gerontol A Biol Sci Med Sci. 2010;65:1086–92.  https://doi.org/10.1093/gerona/glq077.CrossRefGoogle Scholar
  35. 35.
    Jankovic J. Atomoxetine for freezing of gait in Parkinson disease. J Neurol Sci. 2009;284:177–8. doi:S0022-510X(09)00508-5 [pii].  https://doi.org/10.1016/j.jns.2009.03.022.CrossRefPubMedGoogle Scholar
  36. 36.
    Karachi C, et al. Cholinergic mesencephalic neurons are involved in gait and postural disorders in Parkinson disease. J Clin Invest. 2010;120:2745–54.  https://doi.org/10.1172/JCI42642.CrossRefPubMedPubMedCentralGoogle Scholar
  37. 37.
    Kaufmann H, Norcliffe-Kaufmann L, Palma JA. Droxidopa in neurogenic orthostatic hypotension. Expert Rev Cardiovasc Ther. 2015;13:875–91.  https://doi.org/10.1586/14779072.2015.1057504.CrossRefPubMedPubMedCentralGoogle Scholar
  38. 38.
    Kucinski A, de Jong IE, Sarter M. Reducing falls in Parkinson’s disease: interactions between donepezil and the 5-HT6 receptor antagonist idalopirdine on falls in a rat model of impaired cognitive control of complex movements. Eur J Neurosci. 2017;45:217–31.  https://doi.org/10.1111/ejn.13354.CrossRefPubMedGoogle Scholar
  39. 39.
    Kucinski A, Paolone G, Bradshaw M, Albin RL, Sarter M. Modeling fall propensity in Parkinson's disease: deficits in the attentional control of complex movements in rats with cortical-cholinergic and striatal-dopaminergic deafferentation. J Neurosci. 2013;33:16522–39.  https://doi.org/10.1523/JNEUROSCI.2545-13.2013.. 33/42/16522 [pii]CrossRefPubMedPubMedCentralGoogle Scholar
  40. 40.
    Kuhl D, et al. In vivo mapping of cholinergic terminals in normal aging, Alzheimer’s disease, and Parkinson’s disease. Ann Neurol. 1996;40:399–410.CrossRefGoogle Scholar
  41. 41.
    Lambert CS, Philpot RM, Engberg ME, Johns BE, Wecker L. Analysis of gait in rats with olivocerebellar lesions and ability of the nicotinic acetylcholine receptor agonist varenicline to attenuate impairments. Behav Brain Res. 2015;291:342–50.  https://doi.org/10.1016/j.bbr.2015.05.056.CrossRefPubMedPubMedCentralGoogle Scholar
  42. 42.
    Leipzig RM, Cumming RG, Tinetti ME. Drugs and falls in older people: a systematic review and meta-analysis: I. Psychotropic drugs. J Am Geriatr Soc. 1999;47:30–9.CrossRefGoogle Scholar
  43. 43.
    Li Z, Yu Z, Zhang J, Wang J, Sun C, Wang P, Zhang J. Impact of rivastigmine on cognitive dysfunction and falling in Parkinson’s disease. Patients Eur Neurol. 2015;74:86–91.  https://doi.org/10.1159/000438824.CrossRefPubMedGoogle Scholar
  44. 44.
    Litvinenko IV, Odinak MM, Mogil'naya VI, Emelin AY. Efficacy and safety of galantamine (reminyl) for dementia in patients with Parkinson's disease (an open controlled trial). Neurosci Behav Physiol. 2008;38:937–45.  https://doi.org/10.1007/s11055-008-9077-3.CrossRefPubMedGoogle Scholar
  45. 45.
    Lundin-Olsson L, Nyberg L, Gustafson Y. ‘Stops walking when talking’ as a predictor of falls in elderly people. Lancet. 1997;349:617.CrossRefGoogle Scholar
  46. 46.
    Luukinen H, Koski K, Laippala P, Kivela SL. Predictors for recurrent falls among the home-dwelling elderly. Scand J Prim Health Care. 1995;13:294–9.CrossRefGoogle Scholar
  47. 47.
    Machado-Duque ME, Castano-Montoya JP, Medina-Morales DA, Castro-Rodriguez A, Gonzalez-Montoya A, Machado-Alba JE. Association between the use of benzodiazepines and opioids with the risk of falls and hip fractures in older adults. Int Psychogeriatr. 2017:1–6.  https://doi.org/10.1017/S1041610217002745.CrossRefGoogle Scholar
  48. 48.
    Mak MK, Auyeung MM. The mini-BESTest can predict parkinsonian recurrent fallers: a 6-month prospective study. J Rehabil Med. 2013;45:565–71.  https://doi.org/10.2340/16501977-1144.CrossRefGoogle Scholar
  49. 49.
    Mancini M, Fling BW, Gendreau A, Lapidus J, Horak FB, Chung K, Nutt JG. Effect of augmenting cholinergic function on gait and balance. BMC Neurol. 2015;15:264.  https://doi.org/10.1186/s12883-015-0523-x.CrossRefPubMedPubMedCentralGoogle Scholar
  50. 50.
    Mancini M, Salarian A, Carlson-Kuhta P, Zampieri C, King L, Chiari L, Horak FB. ISway: a sensitive, valid and reliable measure of postural control. J Neuroeng Rehabil. 2012;9:59.  https://doi.org/10.1186/1743-0003-9-59.CrossRefPubMedPubMedCentralGoogle Scholar
  51. 51.
    Marcum ZA, et al. Antidepressant use and recurrent falls in community-dwelling older adults: findings from the health ABC study. Ann Pharmacother. 2016a;50:525–33.  https://doi.org/10.1177/1060028016644466.CrossRefPubMedPubMedCentralGoogle Scholar
  52. 52.
    Marcum ZA, et al. Anticholinergic medication use and falls in postmenopausal women: findings from the women’s health initiative cohort study. BMC Geriatr. 2016b;16:76.  https://doi.org/10.1186/s12877-016-0251-0.CrossRefPubMedPubMedCentralGoogle Scholar
  53. 53.
    Montero-Odasso M, et al. Donepezil improves gait performance in older adults with mild Alzheimer’s disease: a phase II clinical trial. J Alzheimers Dis. 2015;43:193–9.  https://doi.org/10.3233/JAD-140759.CrossRefGoogle Scholar
  54. 54.
    Montero-Odasso M, Speechley M. Falls in cognitively impaired older adults: implications for risk assessment and prevention. J Am Geriatr Soc. 2018;66:367–75.  https://doi.org/10.1111/jgs.15219.CrossRefGoogle Scholar
  55. 55.
    Montero-Odasso M, Wells J, Borrie M. Can cognitive enhancers reduce the risk of falls in people with dementia? An open-label study with controls. J Am Geriatr Soc. 2009;57:359–60. doi:JGS2085 [pii].  https://doi.org/10.1111/j.1532-5415.2009.02085.x.CrossRefPubMedPubMedCentralGoogle Scholar
  56. 56.
    Montero-Odasso MM, et al. Association of dual-task gait with incident dementia in mild cognitive impairment: results from the gait and brain study. JAMA Neurol. 2017;74:857–65.  https://doi.org/10.1001/jamaneurol.2017.0643.CrossRefPubMedPubMedCentralGoogle Scholar
  57. 57.
    Moreau C, et al. Methylphenidate for gait hypokinesia and freezing in patients with Parkinson’s disease undergoing subthalamic stimulation: a multicentre, parallel, randomised, placebo-controlled trial. Lancet Neurol. 2012;11:589–96.  https://doi.org/10.1016/S1474-4422(12)70106-0.. S1474-4422(12)70106-0 [pii]CrossRefPubMedGoogle Scholar
  58. 58.
    Muller ML, Albin RL, Kotagal V, Koeppe RA, Scott PJ, Frey KA, Bohnen NI. Thalamic cholinergic innervation and postural sensory integration function in Parkinson’s disease. Brain. 2013;136:3282–9.  https://doi.org/10.1093/brain/awt247.. awt247 [pii]CrossRefPubMedPubMedCentralGoogle Scholar
  59. 59.
    Muller ML, Bohnen NI, Kotagal V, Scott PJ, Koeppe RA, Frey KA, Albin RL. Clinical markers for identifying cholinergic deficits in Parkinson’s disease. Mov Disord. 2015;30:269–73.  https://doi.org/10.1002/mds.26061.CrossRefPubMedGoogle Scholar
  60. 60.
    Nebes RD, Pollock BG, Halligan EM, Kirshner MA, Houck PR. Serum anticholinergic activity and motor performance in elderly persons. J Gerontol A Biol Sci Med Sci. 2007;62:83–5.CrossRefGoogle Scholar
  61. 61.
    Nevitt MC. Falls in the elderly: risk factors and prevention. In: Masdeu JC, Sudarsky L, Wolfson L, editors. Gait disorders of aging. Philadelphia: Lippincott–Raven; 1997.Google Scholar
  62. 62.
    Nutt JG, Carter JH, Carlson NE. Effects of methylphenidate on response to oral levodopa: a double-blind clinical trial. Arch Neurol. 2007;64:319–23. doi:64/3/319 [pii].  https://doi.org/10.1001/archneur.64.3.319.CrossRefPubMedGoogle Scholar
  63. 63.
    Podsiadlo D, Richardson S. The timed “up & go”: a test of basic functional mobility for frail elderly persons. J Am Geriatr Soc. 1991;39:142–8.CrossRefGoogle Scholar
  64. 64.
    Pollak L, Dobronevsky Y, Prohorov T, Bahunker S, Rabey JM. Low dose methylphenidate improves freezing in advanced Parkinson’s disease during off-state. J Neural Transm Suppl. 2007;72:145–8.CrossRefGoogle Scholar
  65. 65.
    Ray WA, Thapa PB, Gideon P. Benzodiazepines and the risk of falls in nursing home residents. J Am Geriatr Soc. 2000;48:682–5.CrossRefGoogle Scholar
  66. 66.
    Risacher SL, et al. Association between anticholinergic medication use and cognition, brain metabolism, and brain atrophy in cognitively normal older adults. JAMA Neurol. 2016;73:721–32.  https://doi.org/10.1001/jamaneurol.2016.0580.CrossRefPubMedPubMedCentralGoogle Scholar
  67. 67.
    Rubenstein LZ, Josephson KR, Robbins AS. Falls in the nursing home. Ann Intern Med. 1994;121:442–51.CrossRefGoogle Scholar
  68. 68.
    Rubenstein LZ, Powers CM, MacLean CH. Quality indicators for the management and prevention of falls and mobility problems in vulnerable elders. Ann Intern Med. 2001;135:683–93.CrossRefGoogle Scholar
  69. 69.
    Ruxton K, Woodman RJ, Mangoni AA. Drugs with anticholinergic effects and cognitive impairment, falls and all-cause mortality in older adults: a systematic review and meta-analysis. Br J Clin Pharmacol. 2015;80:209–20.  https://doi.org/10.1111/bcp.12617.CrossRefPubMedPubMedCentralGoogle Scholar
  70. 70.
    Salarian A, Horak FB, Zampieri C, Carlson-Kuhta P, Nutt JG, Aminian K. iTUG, a sensitive and reliable measure of mobility. IEEE Trans Neural Syst Rehabil Eng. 2010;18:303–10.  https://doi.org/10.1109/TNSRE.2010.2047606.CrossRefPubMedPubMedCentralGoogle Scholar
  71. 71.
    Sarter M, Albin RL, Kucinski A, Lustig C. Where attention falls: increased risk of falls from the converging impact of cortical cholinergic and midbrain dopamine loss on striatal function. Exp Neurol. 2014;257C:120–9.  https://doi.org/10.1016/j.expneurol.2014.04.032.CrossRefGoogle Scholar
  72. 72.
    Sarter M, Parikh V, Howe WM. nAChR agonist-induced cognition enhancement: integration of cognitive and neuronal mechanisms. Biochem Pharmacol. 2009;78:658–67. doi:S0006-2952(09)00305-0 [pii].  https://doi.org/10.1016/j.bcp.2009.04.019.CrossRefPubMedPubMedCentralGoogle Scholar
  73. 73.
    Shaw FE. Falls in cognitive impairment and dementia. Clin Geriatr Med. 2002;18:159–73.CrossRefGoogle Scholar
  74. 74.
    Shumway-Cook A, Woollacott MH. Motor control: theory and practical applications. Baltimore: Lippincott Williams & Wilkins; 1995.Google Scholar
  75. 75.
    Studenski S, Duncan PW, Chandler J. Postural responses and effector factors in persons with unexplained falls: results and methodologic issues. J Am Geriatr Soc. 1991;39:229–34.CrossRefGoogle Scholar
  76. 76.
    Thapa PB, Gideon P, Cost TW, Milam AB, Ray WA. Antidepressants and the risk of falls among nursing home residents. N Engl J Med. 1998;339:875–82.  https://doi.org/10.1056/NEJM199809243391303.CrossRefPubMedGoogle Scholar
  77. 77.
    Tinetti ME, Speechley M, Ginter SF. Risk factors for falls among elderly persons living in the community. N Engl J Med. 1988;319:1701–7.CrossRefGoogle Scholar
  78. 78.
    Volkow ND, et al. Dopamine transporters decrease with age in healthy subjects. J Nucl Med. 1996;37:554–8.PubMedGoogle Scholar
  79. 79.
    Whitehouse PJ, Martino AM, Wagster MV, Price DL, Mayeux R, Atack JR, Kellar KJ. Reductions in [3H]nicotinic acetylcholine binding in Alzheimer’s disease and Parkinson’s disease: an autoradiographic study. Neurology. 1988;38:720–3.CrossRefGoogle Scholar
  80. 80.
    Whitehouse PJ, Price DL, Clark AW, Coyle JT, DeLong MR. Alzheimer’s disease: evidence for selective loss of cholinergic neurons in the nucleus basalis. Ann Neurol. 1981;10:122–6.CrossRefGoogle Scholar
  81. 81.
    Wilkinson D, Windfeld K, Colding-Jorgensen E. Safety and efficacy of idalopirdine, a 5-HT6 receptor antagonist, in patients with moderate Alzheimer’s disease (LADDER): a randomised, double-blind, placebo-controlled phase 2 trial. Lancet Neurol. 2014;13:1092–9.  https://doi.org/10.1016/S1474-4422(14)70198-X.CrossRefPubMedGoogle Scholar
  82. 82.
    Wong KK, Muller ML, Kuwabara H, Studenski SA, Bohnen NI. Olfactory loss and nigrostriatal dopaminergic denervation in the elderly. Neurosci Lett. 2010;484:163–7. doi:S0304-3940(10)01083-9 [pii].  https://doi.org/10.1016/j.neulet.2010.08.037.CrossRefPubMedGoogle Scholar
  83. 83.
    Wood BH, Bilclough JA, Bowron A, Walker RW. Incidence and prediction of falls in Parkinson’s disease: a prospective multidisciplinary study. J Neurol Neurosurg Psychiatry. 2002;72:721–5.CrossRefGoogle Scholar
  84. 84.
    Woollacott MH, Shumway-Cook A, Nashner LM. Aging and posture control: changes in sensory organization and muscular coordination. Int J Aging Hum Dev. 1986;23:97–114.CrossRefGoogle Scholar
  85. 85.
    Wrisley DM, Marchetti GF, Kuharsky DK, Whitney SL. Reliability, internal consistency, and validity of data obtained with the functional gait assessment. Phys Ther. 2004;84:906–18.PubMedGoogle Scholar
  86. 86.
    Yogev-Seligmann G, Hausdorff JM, Giladi N. The role of executive function and attention in gait. Mov Disord. 2008;23:329–42.CrossRefGoogle Scholar
  87. 87.
    Zia A, Kamaruzzaman S, Myint PK, Tan MP. Anticholinergic burden is associated with recurrent and injurious falls in older individuals. Maturitas. 2016;84:32–7.  https://doi.org/10.1016/j.maturitas.2015.10.009.CrossRefPubMedGoogle Scholar

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Authors and Affiliations

  • Nicolaas I. Bohnen
    • 1
    • 2
    • 3
    • 4
    • 5
    Email author
  • Martijn L. T. M. Müller
    • 1
    • 4
  1. 1.Department of RadiologyUniversity of MichiganAnn ArborUSA
  2. 2.Department of NeurologyUniversity of MichiganAnn ArborUSA
  3. 3.Veterans Administration Ann Arbor Healthcare SystemAnn ArborUSA
  4. 4.Morris K. Udall Center of Excellence for Parkinson’s Disease Research, University of MichiganAnn ArborUSA
  5. 5.Functional Neuroimaging, Cognitive and Mobility LaboratoryUniversity of Michigan, Domino’s FarmsAnn ArborUSA

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