Mild Parkinsonian Signs in a Hospital-based Cohort of Mild Cognitive Impairment Types: A Cross-sectional Study

Author(s): Cecilia Camarda*, Paola Torelli, Carmela Pipia, Iacopo Battaglini, Delia Azzarello, Rosamaria Rosano, Caterina Claudia Ventimiglia, Gianluca Sottile, Giovanna Cilluffo, Rosolino Camarda

Journal Name: Current Alzheimer Research

Volume 16 , Issue 7 , 2019

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Background: Mild Parkinsonian Signs (MPS) have been associated with Mild Cognitive Impairment (MCI) types with conflicting results.

Objective: To investigate the association of individual MPS with different MCI types using logistic ridge regression analysis, and to evaluate for each MCI type, the association of MPS with caudate atrophy, global cerebral atrophy, and the topographical location of White Matter Hyperintensities (WMH), and lacunes.

Methods: A cross-sectional study was performed among 1,168 subjects with different types of MCI aged 45-97 (70,52 ± 9,41) years, who underwent brain MRI. WMH were assessed through two visual rating scales. The number and location of lacunes were also rated. Atrophy of the caudate nuclei and global cerebral atrophy were assessed through the bicaudate ratio, and the lateral ventricles to brain ratio, respectively. Apolipoprotein E (APOE) genotypes were also assessed. Using the items of the motor section of the Unified Parkinson’s Disease Rating Scale, tremor, rigidity, bradykinesia, and gait/balance/axial dysfunction were evaluated.

Results: Bradykinesia, and gait/balance/axial dysfunction were the MPS more frequently encountered followed by rigidity, and tremor. MPS were present in both amnestic and non-amnestic MCI types, and were associated with WMH, lacunes, bicaudate ratio, and lateral ventricles to brain ratio.

Conclusion: MPS are present in both amnestic and non-amnestic MCI types, particularly in those multiple domain, and carrying the APOE ε4 allele. Cortical and subcortical vascular and atrophic processes contribute to MPS. Long prospective studies are needed to disentangle the contribution of MPS to the conversion from MCI to dementia.

Keywords: Mild parkinsonian signs, mild cognitive impairment types, white matter hyperintensities, lacunes, caudate atrophy, global cerebral atrophy.

Louis ED, Bennett DA. Mild Parkinsonian signs: An overview of an emerging concept. Mov Disord 22(12): 1681-8. (2007)
[] [PMID: 17534951]
Louis ED, Luchsinger JA. History of vascular disease and mild parkinsonian signs in community-dwelling elderly individuals. Arch Neurol 63(5): 717-22. (2006)
[] [PMID: 16682541]
Louis ED, Schupf N, Manly J, Marder K, Tang MX, Mayeux R. Association between mild parkinsonian signs and mild cognitive impairment in a community. Neurology 64(7): 1157-61. (2005)
[] [PMID: 15824340]
Boyle PA, Wilson RS, Aggarwal NT, et al. Parkinsonian signs in subjects with mild cognitive impairment. Neurology 65(12): 1901-6. (2005)
[] [PMID: 16380610]
Rozzini L, Chilovi BV, Bertoletti E, Conti M, Delrio I, Trabucchi M, et al. Mild parkinsonian signs and psycho-behavioral symptoms in subjects with mild cognitive impairment. Int Psychogeriatr 20(1): 86-95. (2008)
[] [PMID: 17868495]
Uemura Y, Wada-Isoe K, Nakashita S, Nakashima K. Depression and cognitive impairment in patients with mild parkinsonian signs. Acta Neurol Scand 128(3): 153-9. (2013)
[] [PMID: 23397887]
Wilson RS, Schneider JA, Bienias JL, Evans DA, Bennett DA. Parkinsonianlike signs and risk of incident Alzheimer disease in older persons. Arch Neurol 60(4): 539-44. (2003)
[] [PMID: 12707067]
Louis ED, Tang MX, Schupf N. Mild parkinsonian signs are associated with increased risk of dementia in a prospective, population-based study of elders. Mov Disord 25(2): 172-8. (2010)
[] [PMID: 20077482]
Ross GW, Petrovitch H, Abbott RD, Nelson J, Markesbery W, Davis D, et al. Parkinsonian signs and substantia nigra neuron density in decendents elders without PD. Ann Neurol 56(4): 532-9. (2004)
[] [PMID: 15389895]
Rosano C, Bennett DA, Newman AB, Venkatraman V, Yaffe K, Harris T, et al. Patterns of focal gray matter atrophy are associated with bradykinesia and gait disturbances in older adults. J Gerontol A Biol Sci Med Sci 67(9): 957-62. (2012)
[] [PMID: 22367436]
Reitz C, Trenkwalder C, Kretzschmar K, Roesler AV, Eckardstein A, Berger K. Relation of cerebral small-vessel disease and brain atrophy to mild Parkinsonism in the elderly. Mov Disord 21(11): 1914-9. (2006)
[] [PMID: 16960865]
de Laat KF, van Norden AG, Gons RA, van Uden IW, Zwiers MP, Bloem BR, et al. Cerebral white matter lesions and lacunar infarcts contribute to the presence of mild parkinsonian signs. Stroke 43(10): 2574-9. (2012)
[] [PMID: 22858727]
de Laat KF, van den Berg HAC, van Norden AGW, Gons RAR, Olde Rikkert MGM, de Leeuw FE. Microbleeds are independently related to gait disturbances in elderly individuals with cerebral small vessel disease. Stroke 42(2): 494-7. (2011)
[] [PMID: 21164137]
Hatate J, Miwa K, Matsumoto M, Sasaki T, Yagita Y, Sakaguchi M, et al. Association between cerebral small vessel diseases and mild parkinsonian signs in the elderly with vascular risk factors. Parkinsonism Relat Disord 26: 29-34. (2016)
[] [PMID: 26949060]
Rosso AL, Bohnen NI, Launer LJ, Aizenstein HJ, Yaffe K, Rosano C. Vascular and dopaminergic contributors to mild parkinsonian signs in older adults. Neurology 90(3): e223-9. (2018)
[] [PMID: 29247072]
Pantoni L. Cerebral small vessel disease: from pathogenesis and clinical characteristics to therapeutic challenges. Lancet Neurol 9(7): 689-701. (2010)
[] [PMID: 20610345]
Petersen RC, Smith GE, Waring SC, Ivnik RJ, Tangalos EG, Kokmen E. Mild cognitive impairment: clinical characterization and outcome. Arch Neurol 56(3): 303-8. (1999)
[] [PMID: 10190820]
Petersen RC. Mild cognitive impairment as a diagnostic entity. J Intern Med 256(3): 183-94. (2004)
[] [PMID: 15324362]
Albert MS, DeKosky ST, Dickson D, Dubois B, Feldman HH, Fox NC, et al. The diagnosis of mild cognitive impairment due to Alzheimer’s disease: recommendations from the National Institute on Aging-Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer’s disease. Alzheimers Dement 7(3): 270-9. (2011)
[] [PMID: 21514249]
Raz N, Lindenberger U, Rodrigue KM, Kennedy KM, Head D, Williamson A, et al. Regional brain changes in aging healthy adults: general trends, individual differences and modifiers. Cereb Cortex 15(11): 1676-89. (2005)
[] [PMID: 15703252]
Jack CR Jr, Wiste HJ, Weigand SD, Therneau TM, Knopman DS, Lowe V, et al. Age-specific and sex-specific prevalence of cerebral β-amyloidosis, tauopathy, and neurodegeneration in cognitively unimpaired individuals aged 50-95 years: a cross-sectional study. Lancet Neurol 16(6): 435-44. (2017)
[] [PMID: 28456479]
Jansen WJ, Ossenkoppele R, Knol DL, Tijms BM, Scheltens P, Verhey FR, et al. Amyloid Biomarker Study Group. Prevalence of cerebral amyloid pathology in persons without dementia: a meta-analysis. JAMA 313(19): 1924-38. (2015)
[] [PMID: 25988462]
Petersen RC, Aisen P, Boeve BF, Geda YE, Ivnik RJ, Knopman DS, et al. Mild cognitive impairment due to Alzheimer disease in the community. Ann Neurol 74(2): 199-208. (2013)
[PMID: 23686697]
Prins ND, van Dijk EJ, den Heijer T, Vermeer SE, Jolles J, Koudstaal PJ, et al. Cerebral small-vessel disease and decline in information processing speed, executive function and memory. Brain 128(Pt 9): 2034-41. (2005)
[] [PMID: 15947059]
Marchant NL, Reed BR, Sanossian N, Madison CM, Kriger S, Dhada R, et al. The aging brain and cognition: contribution of vascular injury and aβ to mild cognitive dysfunction. JAMA Neurol 70(4): 488-95. (2013)
[] [PMID: 23400560]
Boyle PA, Yu L, Fleischman DA, Leurgans S, Yang J, Wilson RS, et al. White matter hyperintensities, incident mild cognitive impairment, and cognitive decline in old age. Ann Clin Transl Neurol 3(10): 791-800. (2016)
[] [PMID: 27752514]
Duering M, Righart R, Wollenweber FA, Zietemann V, Gesierich B, Dichgans M. Acute infarcts cause focal thinning in remote cortex via degeneration of connecting fiber tracts. Neurology 84(16): 1685-92. (2015)
[] [PMID: 25809303]
Lambert C, Sam Narean J, Benjamin P, Zeestraten E, Barrick TR, Markus HS. Characterising the grey matter correlates of leukoaraiosis in cerebral small vessel disease. Neuroimage Clin 9: 194-205. (2015)
[] [PMID: 26448913]
Thong JY, Hilal S, Wang Y, Soon HW, Dong Y, Collinson SL, et al. Association of silent lacunar infarct with brain atrophy and cognitive impairment. J Neurol Neurosurg Psychiatry 84(11): 1219-25. (2013)
[] [PMID: 23933740]
Habes M, Erus G, Toledo JB, Zhang T, Bryan N, Launer LJ, et al. White matter hyperintensities and imaging patterns of brain ageing in the general population. Brain 139(Pt 4): 1164-79. (2016)
[] [PMID: 26912649]
Marnane M, Al-Jawadi OO, Mortazavi S, Pogorzelec KJ, Wang BW, Feldman HH, et al. Alzheimer’s Disease Neuroimaging Initiative. Periventricular hyperintensities are associated with elevated cerebral amyloid. Neurology 86(6): 535-43. (2016)
[] [PMID: 26747881]
Camarda R, Camarda C, Monastero R, Grimaldi S, Camarda LK, Pipia C, et al. Movements execution in amnestic mild cognitive impairment and Alzheimer’s disease. Behav Neurol 18(3): 135-42. (2007)
[] [PMID: 17726241]
Rizzolatti G, Camarda R. Neural circuits for spatial attention and unilateral neglectNeurophysiological and Neuropsychological aspects of Spatial Neglect Elsevier Science Publisher. Amsterdam: Norh-Holland. 1987; pp. 251-68.
Bahureksa L, Najafi B, Saleh A, Sabbagh M, Coon D, Mohler MJ, et al. The impact of Mild Cognitive Impairment on gait and balance: a systematic review and meta-analysis of studies using instrumented assessment. Gerontology 63(1): 67-83. (2017)
[] [PMID: 27172932]
Camicioli R, Howieson D, Oken B, Sexton G, Kaye J. Motor slowing precedes cognitive impairment in the oldest old. Neurology 50(5): 1496-8. (1998)
[] [PMID: 9596020]
Verghese J, Lipton RB, Hall CB, Kuslansky G, Katz MJ, Buschke H. Abnormality of gait as a predictor of non-Alzheimer’s dementia. N Engl J Med 347(22): 1761-8. (2002)
[] [PMID: 12456852]
Kim YJ, Kwon HK, Lee JM, Cho H, Kim HJ, Park HK, et al. Gray and white matter changes linking cerebral small vessel disease to gait disturbances. Neurology 86(13): 1199-207. (2016)
[] [PMID: 26935893]
Carlson NE, Moore MM, Dame A, et al. Trajectories of brain loss in aging and the development of cognitive impairment. Neurology 70(11): 828-33. (2008)
[] [PMID: 18046010]
Madsen SK, Gutman BA, Joshi SH, Toga AW, Jack CR Jr, Weiner MW, et al. Alzheimer’s Disease Neuroimaging Initiative (ADNI). Mapping ventricular expansion onto cortical gray matter in older adults. Neurobiol Aging 36(1): S32-41. (2015)
[] [PMID: 25311280]
Annweiler C, Beauchet O, Bartha R, Montero-Odasso M. WALK Team-Working group Angers-London for Knowledge. Slow gait in MCI is associated with ventricular enlargement: results from the Gait and Brain Study. J Neural Transm (Vienna) 120(7): 1083-92. (2013)
[] [PMID: 23196981]
Dumurgier J, Crivello F, Mazoyer B, Ahmed I, Tavernier B, Grabli D, et al. MRI atrophy of the caudate nucleus and slower walking speed in the elderly. Neuroimage 60(2): 871-8. (2012)
[] [PMID: 22305950]
Macfarlane MD, Looi JC, Walterfang M, Spulber G, Velakoulis D, Styner M, et al. LADIS Study Group. Shape abnormalities of the caudate nucleus correlate with poorer gait and balance: results from a subset of the LADIS study. Am J Geriatr Psychiatry 23(1): 59-71.e1. (2015)
[] [PMID: 23916546]
Macfarlane MD, Looi JCL, Walterfang M, Spulber G, Velakoulis D, Crisby M, et al. LADIS Study Group Executive dysfunction correlates with caudate nucleus atrophy in patients with white matter changes on MRI: a subset of LADIS. Psychiatry Res 214(1): 16-23. (2013)
[] [PMID: 23916538]
Alexander GE, DeLong MR, Strick PL. Parallel organization of functionally segregated circuits linking basal ganglia and cortex. Annu Rev Neurosci 9: 357-81. (1986)
[] [PMID: 3085570]
Caligiore D, Pezzulo G, Baldassarre G, Bostan AC, Strick PL, Doya K, et al. Consensus paper: towards a systems-level view of cerebellar function: the interplay between cerebellum, basal ganglia, and cortex. Cerebellum 16(1): 203-29. (2017)
[] [PMID: 26873754]
Bell PT, Shine JM. Subcortical contributions to large-scale network communication. Neurosci Biobehav Rev 71: 313-22. (2016)
[] [PMID: 27590830]
Smith EE, O’Donnell M, Dagenais G, Lear SA, Wielgosz A, Sharma M, et al. PURE Investigators.Early cerebral small vessel disease and brain volume, cognition, and gait. Ann Neurol 77(2): 251-61. (2015)
[] [PMID: 25428654]
Camarda C, Torelli P, Camarda R, Battaglini I, Gagliardo C, Monastero R. Isolated, subtle neurological abnormalities in cognitively and neurologically healthy aging subjects. J Neurol 262: 1328-39. (2015)
[] [PMID: 25825125]
Folstein MF, Folstein SE, McHugh PR. “Mini-mental state”. A practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res 12(3): 189-98. (1975)
[] [PMID: 1202204]
Morris JC. The Clinical Dementia Rating (CDR): current version and scoring rules. Neurology 43(11): 2412-4. (1993)
[] [PMID: 8232972]
Katz S, Ford AB, Moskowitz RW, Jackson BA, Jaffe MW. Studies of illness in the aged. The index of ADL: a standardized measure of biological and psychosocial function. JAMA 185: 914-9. (1963)
[] [PMID: 14044222]
Lawton MP, Brody EM. Assessment of older people: self-maintaining and instrumental activities of daily living. Gerontologist 9(3): 179-86. (1969)
[] [PMID: 5349366]
Hixson JE, Vernier DT. Restriction isotyping of human apolipoprotein E by gene amplification and cleavage with HhaI. J Lipid Res 31(3): 545-8. (1990)
[PMID: 2341813]
Fahn S, Marsden CD, Goldstein M, Calne DB, Eds. Fahn S, Elton RL and the members of the UPDRS development committee Unified Parkinson’s Disease Rating Scale Recent Developments in Parkinson’s Disease. London: MacMillan Healthcare Information. 1987; pp. 153-63.
Camarda C, Pipia C, Azzarello D, Battaglini I, Romeo G, Chiodi M, et al. Vascular risk factors, vascular diseases, and imaging findings in a hospital-based cohort of mild cognitive impairment types. Curr Alzheimer Res 15(7): 679-90. (2018)
[] [PMID: 29357798]
Wardlaw JM, Smith EE, Biessels GJ, Cordonnier C, Fazekas F, Frayne R, et al. STandards for ReportIng Vascular changes on nEuroimaging (STRIVE v1). Neuroimaging standards for research into small vessel disease and its contribution to ageing and neurodegeneration. Lancet Neurol 12(8): 822-38. (2013)
[] [PMID: 23867200]
Wahlund LO, Barkhof F, Fazekas F, Bronge L, Augustin M, Sjögren M, et al. European task force on age-related white matter changes. A new rating scale for age-related white matter changes applicable to MRI and CT. Stroke 32(6): 1318-22. (2001)
[] [PMID: 11387493]
Fazekas F, Chawluk JB, Alavi A, Hurtig HI, Zimmerman RA. MR signal abnormalities at 1.5 T in Alzheimer’s dementia and normal aging. AJR Am J Roentgenol 149(2): 351-6. (1987)
[] [PMID: 3496763]
Hoerl AE, Kennard RW. Ridge regression: biased estimation for nonorthogonal problems. Technometrics 12: 55-67. (1970)
El-Dereny M, Rashwan NI. Solving multicollinearity problem using ridge regression models. Int J Contemp Math Sciences 6: 585-600. (2011)
Goeman JJ. L1 penalized estimation in the Cox proportional hazards model. Biom J 52(1): 70-84. (2010)
[PMID: 19937997]
Gelb DJ, Oliver E, Gilman S. Diagnostic criteria for Parkinson disease. Arch Neurol 56(1): 33-9. (1999)
[] [PMID: 9923759]
Villeneuve S, Reed BR, Madison CM, Wirth M, Marchant NL, Kriger S, et al. Vascular risk and Aβ interact to reduce cortical thickness in AD vulnerable brain regions. Neurology 83(1): 40-7. (2014)
[] [PMID: 24907234]
Romero JR, Beiser A, Seshadri S, Benjamin EJ, Polak JF, Vasan RS, et al. Carotid artery atherosclerosis, MRI indices of brain ischemia, aging, and cognitive impairment: the Framingham study. Stroke 40(5): 1590-6. (2009)
[] [PMID: 19265054]
Viticchi G, Falsetti L, Vernieri F, Altamura C, Bartolini M, Luzzi S, et al. Vascular predictors of cognitive decline in patients with mild cognitive impairment. Neurobiol Aging 33(6): 1127.e1-9. (2012)
[] [PMID: 22217417]
Lee HK, Lee YM, Park JM, Lee BD, Moon ES, Chung YI. Amnestic multiple cognitive domains impairment and periventricular white matter hyperintensities are independently predictive factors progression to dementia in mild cognitive impairment. Int J Geriatr Psychiatry 29(5): 526-32. (2014)
[] [PMID: 24123391]
Kamali A, Flanders AE, Brody J, Hunter JV, Hasan KM. Tracing superior longitudinal fasciculus connectivity in the human brain using high resolution diffusion tensor tractography. Brain Struct Funct 219(1): 269-81. (2014)
[] [PMID: 23288254]
Schmahmann JD. Disorders of the cerebellum: ataxia, dysmetria of thought, and the cerebellar cognitive affective syndrome. J Neuropsychiatry Clin Neurosci 16(3): 367-78. (2004)
[] [PMID: 15377747]
Gunning-Dixon FM, Raz N. Neuroanatomical correlates of selected executive functions in middle-aged and older adults: a prospective MRI study. Neuropsychologia 41(14): 1929-41. (2003)
[] [PMID: 14572526]
Verghese J, Wang C, Lipton RB, Holtzer R, Xue X. Quantitative gait dysfunction and risk of cognitive decline and dementia. J Neurol Neurosurg Psychiatry 78(9): 929-35. (2007)
[] [PMID: 17237140]
Rosano C, Aizenstein H, Brach J, Longenberger A, Studenski S, Newman AB. Special article: gait measures indicate underlying focal gray matter atrophy in the brain of older adults. J Gerontol A Biol Sci Med Sci 63(12): 1380-8. (2008)
[] [PMID: 19126852]
Rowe CC, Ng S, Ackermann U, Gong SJ, Pike K, Savage G, et al. Imaging beta-amyloid burden in aging and dementia. Neurology 68(20): 1718-25. (2007)
[] [PMID: 17502554]
Takakusaki K. Neurophysiology of gait: from the spinal cord to the frontal lobe. Mov Disord 28(11): 1483-91. (2013)
[] [PMID: 24132836]
de Groot M, Verhaaren BF, de Boer R, Klein S, Hofman A, van der Lugt A, et al. Changes in normal-appearing white matter precede development of white matter lesions. Stroke 44(4): 1037-42. (2013)
[] [PMID: 23429507]
Boone KB, Miller BL, Lesser IM, Mehringer CM, Hill-Gutierrez E, Goldberg MA, et al. Neuropsychological correlates of white-matter lesions in healthy elderly subjects. A threshold effect. Arch Neurol 49(5): 549-54. (1992)
[] [PMID: 1580819]
Biesbroek JM, Weaver NA, Biessels GJ. Lesion location and cognitive impact of cerebral small vessel disease. Clin Sci (Lond) 131(8): 715-28. (2017)
[] [PMID: 28385827]
Wolk DA, Price JC, Saxton JA, Snitz BE, James JA, Lopez OL, et al. Amyloid imaging in mild cognitive impairment subtypes. Ann Neurol 65(5): 557-68. (2009)
[] [PMID: 19475670]
Vos SJ, van Rossum IA, Verhey F, Knol DL, Soininen H, Wahlund LO, et al. Prediction of Alzheimer disease in subjects with amnestic and nonamnestic MCI. Neurology 80(12): 1124-32. (2013)
[] [PMID: 23446677]
Kemppainen NM, Aalto S, Wilson IA, Någren K, Helin S, Brück A, et al. PET amyloid ligand [11C]PIB uptake is increased in mild cognitive impairment. Neurology 68(19): 1603-6. (2007)
[] [PMID: 17485647]
Koivunen J, Scheinin N, Virta JR, Aalto S, Vahlberg T, Någren K, et al. Amyloid PET imaging in patients with mild cognitive impairment: a 2-year follow-up study. Neurology 76(12): 1085-90. (2011)
[] [PMID: 21325653]
Okello A, Koivunen J, Edison P, Archer HA, Turkheimer FE, Någren K, et al. Conversion of amyloid positive and negative MCI to AD over 3 years: an 11C-PIB PET study. Neurology 73(10): 754-60. (2009)
[] [PMID: 19587325]
Verghese J, Holtzer R, Wang C, Katz MJ, Barzilai N, Lipton RB. Role of APOE genotype in gait decline and disability in aging. J Gerontol A Biol Sci Med Sci 68(11): 1395-401. (2013)
[] [PMID: 23902934]
Doraiswamy PM, Patterson L, Na C, Husain MM, Boyko O, McDonald WM, et al. Bicaudate index on magnetic resonance imaging: effects of normal aging. J Geriatr Psychiatry Neurol 7(1): 13-7. (1994)
[] [PMID: 8192824]
Nestor SM, Rupsingh R, Borrie M, Smith M, Accomazzi V, Wells JL, et al. Alzheimer’s Disease Neuroimaging Initiative. Ventricular enlargement as a possible measure of Alzheimer’s disease progression validated using the Alzheimer’s disease neuroimaging initiative database. Brain 131(Pt 9): 2443-54. (2008)
[] [PMID: 18669512]
Yates PA, Desmond PM, Phal PM, Steward C, Szoeke C, Salvado O, et al. AIBL Research Group.Incidence of cerebral microbleeds in preclinical Alzheimer disease. Neurology 82(14): 1266-73. (2014)
[] [PMID: 24623839]

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Year: 2019
Published on: 04 September, 2019
Page: [633 - 649]
Pages: 17
DOI: 10.2174/1567205016666190726100744
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