Abstract
Pure vascular parkinsonism without evidence of nigral Lewy body pathology may occur as a distinct clinicopathological entity, but a much more frequent occurrence is the comorbid presence of age-associated white matter lesions (WMLs) in idiopathic Parkinson disease (PD). WMLs are associated with motor and cognitive symptoms in otherwise normal elderly individuals. Comorbid WMLs are, therefore, expected to contribute to clinical symptoms in PD. Studies of WMLs in PD differ with regard to methods of assessment of WML burden and the patient populations selected for analysis, but converging evidence suggests that postural stability and gait motor functions are predominantly affected. WMLs are described to contribute to dementia in Alzheimer disease, and emerging but inconclusive evidence indicates similar effects in PD. In this article, we review the literature addressing the occurrence and impact of WMLs in PD, and suggest that WMLs may exacerbate or contribute to some motor and cognitive deficits associated with PD. We review existing and emerging methods for studying white matter pathology in vivo, and propose future research directions.
Key Points
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White matter lesions (WMLs) correlate with motor and cognitive abnormalities in otherwise normal elderly individuals, and some of these abnormalities overlap with features of Parkinson disease (PD)
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Comorbid WMLs in PD may contribute to motor symptoms—in particular, balance disturbances—possibly by disrupting subcortical–cortical tracts involved in gait and balance
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Most pathobiological emphasis in PD has been on proximal neural systems, but clinical symptom augmentation by comorbid WMLs illustrates the importance of integrity of afferent and efferent subcortical–cortical projections
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Diffusion tensor MRI is a novel imaging modality to study microstructural white matter changes; findings of such changes in early PD are consistent with other evidence of widespread neurodegeneration
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Early prevention or mitigation of comorbid WMLs, perhaps by reducing cerebrovascular or metabolic risk factors, could result in reduced motor and cognitive disability in PD
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References
Murray, M. E. et al. Functional impact of white matter hyperintensities in cognitively normal elderly subjects. Arch. Neurol. 67, 1379–1385 (2010).
Baloh, R. W., Yue, Q., Socotch, T. M. & Jacobson, K. M. White matter lesions and disequilibrium in older people. I. Case–control comparison. Arch. Neurol. 52, 970–974 (1995).
Gunning-Dixon, F. M. & Raz, N. The cognitive correlates of white matter abnormalities in normal aging: a quantitative review. Neuropsychology 14, 224–232 (2000).
Baezner, H. et al. Association of gait and balance disorders with age-related white matter changes: the LADIS study. Neurology 70, 935–942 (2008).
Novak, V. et al. White matter hyperintensities and dynamics of postural control. Magn. Reson. Imaging 27, 752–759 (2009).
Tullberg, M. et al. White matter lesions impair frontal lobe function regardless of their location. Neurology 63, 246–253 (2004).
Prins, N. D. et al. Cerebral small-vessel disease and decline in information processing speed, executive function and memory. Brain 128, 2034–2041 (2005).
de Laat, K. F. et al. Loss of white matter integrity is associated with gait disorders in cerebral small vessel disease. Brain 134, 73–83 (2011).
Pantoni, L. & Garcia, J. H. Pathogenesis of leukoaraiosis. Stroke 28, 652–659 (1997).
Young, V. G., Halliday, G. M. & Kril, J. J. Neuropathologic correlates of white matter hyperintensities. Neurology 71, 804–811 (2008).
Black, S., Gao, F. & Bilbao, J. Understanding white matter disease: imaging–pathological correlations in vascular cognitive impairment. Stroke 40 (3 Suppl.), S48–S52 (2009).
van Swieten, J. C. et al. Periventricular lesions in the white matter on magnetic resonance imaging in the elderly. A morphometric correlation with arteriolosclerosis and dilated perivascular spaces. Brain 114, 761–774 (1991).
Fazekas, F. et al. Pathologic correlates of incidental MRI white matter signal hyperintensities. Neurology 43, 1683–1689 (1993).
Leys, D. et al. Could Wallerian degeneration contribute to “leuko-araiosis” in subjects free of any vascular disorder? J. Neurol. Neurosurg. Psychiatry 54, 46–50 (1991).
Ballard, C. et al. Neurocardiovascular instability, hypotensive episodes, and MRI lesions in neurodegenerative dementia. Ann. N. Y. Acad. Sci. 903, 442–445 (2000).
Wersching, H. et al. Serum C-reactive protein is linked to cerebral microstructural integrity and cognitive function. Neurology 74, 1022–1029 (2010).
Pieters, B. et al. Periventricular white matter lucencies relate to low vitamin B12 levels in patients with small vessel stroke. Stroke 40, 1623–1626 (2009).
Demirkiran, M., Bozdemir, H. & Sarica, Y. Vascular parkinsonism: a distinct, heterogeneous clinical entity. Acta Neurol. Scand. 104, 63–67 (2001).
Thanvi, B., Lo, N. & Robinson, T. Vascular parkinsonism—an important cause of parkinsonism in older people. Age Ageing 34, 114–119 (2005).
Zijlmans, J. C., Daniel, S. E., Hughes, A. J., Revesz, T. & Lees, A. J. Clinicopathological investigation of vascular parkinsonism, including clinical criteria for diagnosis. Mov. Disord. 19, 630–640 (2004).
Jellinger, K. A. The pathology of Parkinson's disease. Adv. Neurol. 86, 55–72 (2001).
Hughes, A. J., Daniel, S. E., Kilford, L. & Lees, A. J. Accuracy of clinical diagnosis of idiopathic Parkinson's disease: a clinicopathologic study of 100 cases. J. Neurol. Neurosurg. Psychiatry 55, 181–184 (1992).
Jellinger, K. A. Prevalence of cerebrovascular lesions in Parkinson's disease. A postmortem study. Acta Neuropathol. 105, 415–419 (2003).
Choi, S. A. et al. Are there differences in cerebral white matter lesion burdens between Parkinson's disease patients with or without dementia? Acta Neuropathol. 119, 147–149 (2010).
Sohn, Y. H. & Kim, J. S. The influence of white matter hyperintensities on the clinical features of Parkinson's disease. Yonsei Med. J. 39, 50–55 (1998).
Slawek, J. et al. The influence of vascular risk factors and white matter hyperintensities on the degree of cognitive impairment in Parkinson's disease. Neurol. Neurochir. Pol. 42, 505–512 (2008).
Lee, S. J. et al. The severity of leukoaraiosis correlates with the clinical phenotype of Parkinson's disease. Arch. Gerontol. Geriatr. 49, 255–259 (2009).
Stern, M. B., Braffman, B. H., Skolnick, B. E., Hurtig, H. I. & Grossman, R. I. Magnetic resonance imaging in Parkinson's disease and parkinsonian syndromes. Neurology 39, 1524–1526 (1989).
Piccini, P. et al. White matter hyperintensities in Parkinson's disease. Clinical correlations. Arch. Neurol. 52, 191–194 (1995).
Van Rossum, E. et al. The level of physical activity in patients with Parkinson's disease [abstract P2.096]. Parkinsonism Relat. Disord. 14 (Suppl. 1), S67–S68 (2008).
Acharya, H. J., Bouchard, T. P., Emery, D. J. & Camicioli, R. M. Axial signs and magnetic resonance imaging correlates in Parkinson's disease. Can. J. Neurol. Sci. 34, 56–61 (2007).
Dalaker, T. O. et al. Brain atrophy and white matter hyperintensities in early Parkinson's disease. Mov. Disord. 24, 2233–2241 (2009).
Joseph, J. A., Roth, G. S. & Strong, R. The striatum, a microcosm for the examination of age-related alterations in the CNS: a selected review. Rev. Biol. Res. Aging 4, 181–199 (1990).
Volkow, N. D. et al. Dopamine transporters decrease with age in healthy subjects. J. Nucl. Med. 37, 554–558 (1996).
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. 20, 415–455 (1973).
Fearnley, J. M. & Lees, A. J. Ageing and Parkinson's disease: Substantia nigra regional selectivity. Brain 114, 2283–2301 (1991).
Bohnen, N. I. et al. Positron emission tomography of monoaminergic vesicular binding in aging and Parkinson disease. J. Cereb. Blood Flow Metab. 26, 1198–1212 (2006).
Louis, E. D. et al. Quantitative brain measurements in community-dwelling elderly persons with mild parkinsonian signs. Arch. Neurol. 65, 1649–1654 (2008).
Brant-Zawadzki, M. et al. MR imaging of the aging brain: patchy white-matter lesions and dementia. Am. J. Neuroradiol. 6, 675–682 (1985).
Fazekas, F., Chawluk, J. B., Alavi, A., Hurtig, H. I. & Zimmerman, R. A. MR signal abnormalities at 1.5 T in Alzheimer's dementia and normal aging. AJR Am. J. Roentgenol. 149, 351–356 (1987).
Longstreth, W. T. Jr et al. Clinical correlates of white matter findings on cranial magnetic resonance imaging of 3301 elderly people: the cardiovascular health study. Stroke 27, 1274–1282 (1996).
Scheltens, P. et al. A semiquantative rating scale for the assessment of signal hyperintensities on magnetic resonance imaging. J. Neurol. Sci. 114, 7–12 (1993).
DeCarli, C., Fletcher, E., Ramey, V., Harvey, D. & Jagust, W. J. Anatomical mapping of white matter hyperintensities (WMH): exploring the relationships between periventricular WMH, deep WMH, and total WMH burden. Stroke 36, 50–55 (2005).
Barkhof, F. & Scheltens, P. Is the whole brain periventricular? J. Neurol. Neurosurg. Psychiatry 77, 143–144 (2006).
Bohnen, N. I., Muller, M. L., Kuwabara, H., Constantine, G. M. & Studenski, S. A. Age-associated leukoaraiosis and cortical cholinergic deafferentation. Neurology 72, 1411–1416 (2009).
de Boer, R. et al. White matter lesion extension to automatic brain tissue segmentation on MRI. Neuroimage 45, 1151–1161 (2009).
Bohnen, N. I., Bogan, C. W. & Müller, M. L. Frontal and periventricular brain white matter lesions and cortical deafferentation of cholinergic and other neuromodulatory axonal projections. Eur. Neurol. J. I, 33–40 (2009).
Sugihara, S., Kinoshita, T., Matsusue, E., Fujii, S. & Ogawa, T. Usefulness of diffusion tensor imaging of white matter in Alzheimer disease and vascular dementia. Acta Radiol. 45, 658–663 (2004).
Gattellaro, G. et al. White matter involvement in idiopathic Parkinson disease: a diffusion tensor imaging study. AJNR Am. J. Neuroradiol. 30, 1222–1226 (2009).
Karagulle Kendi, A. T., Lehericy, S., Luciana, M., Ugurbil, K. & Tuite, P. Altered diffusion in the frontal lobe in Parkinson disease. AJNR Am. J. Neuroradiol. 29, 501–505 (2008).
Lee, D. Y. et al. Vascular and degenerative processes differentially affect regional interhemispheric connections in normal aging, mild cognitive impairment, and Alzheimer disease. Stroke 41, 1791–1797 (2010).
Slawek, J. et al. Vascular risk factors do not contribute to motor and cognitive impairment in Parkinson's disease. Parkinsonism Relat. Disord. 16, 73–74 (2010).
Albin, R. L. et al. White matter lesions augment motor impairments of nigrostriatal dopaminergic denervation in Parkinson disease [abstract S53.004]. Neurology 74 (Suppl. 2), A500 (2010).
Mayeux, R. et al. An estimate of the incidence of dementia in idiopathic Parkinson's disease. Neurology 40, 1513–1517 (1990).
Marder, K., Tang, M.-X., Côté, L., Stern, Y. & Mayeux, R. The frequency and associated risk factors for dementia in patients with Parkinson's disease. Arch. Neurol. 52, 695–701 (1995).
Aarsland, D. & Kurz, M. W. The epidemiology of dementia associated with Parkinson disease. J. Neurol. Sci. 289, 18–22 (2010).
Kuczynski, B. et al. Cognitive and anatomic contributions of metabolic decline in Alzheimer disease and cerebrovascular disease. Arch. Neurol. 65, 650–655 (2008).
Chui, H. C. et al. Cognitive impact of subcortical vascular and Alzheimer's disease pathology. Ann. Neurol. 60, 677–687 (2006).
Marshall, G. A., Shchelchkov, E., Kaufer, D. I., Ivanco, L. S. & Bohnen, N. I. White matter hyperintensities and cortical acetylcholinesterase activity in parkinsonian dementia. Acta Neurol. Scand. 113, 87–91 (2006).
Burton, E. J., McKeith, I. G., Burn, D. J., Firbank, M. J. & O'Brien, J. T. Progression of white matter hyperintensities in Alzheimer disease, dementia with lewy bodies, and Parkinson disease dementia: a comparison with normal aging. Am. J. Geriatr. Psychiatry 14, 842–849 (2006).
Beyer, M. K., Aarsland, D., Greve, O. J. & Larsen, J. P. Visual rating of white matter hyperintensities in Parkinson's disease. Mov. Disord. 21, 223–229 (2006).
Lee, S. J. et al. Influence of white matter hyperintensities on the cognition of patients with Parkinson disease. Alzheimer Dis. Assoc. Disord. 24, 227–233 (2010).
Dalaker, T. O. et al. White matter hyperintensities do not impact cognitive function in patients with newly diagnosed Parkinson's disease. Neuroimage 47, 2083–2089 (2009).
Meyer, J. S., Huang, J. & Chowdhury, M. H. MRI confirms mild cognitive impairments prodromal for Alzheimer's, vascular and Parkinson–Lewy body dementias. J. Neurol. Sci. 257, 97–104 (2007).
Santangelo, G. et al. Differential neuropsychological profiles in Parkinsonian patients with or without vascular lesions. Mov. Disord. 25, 50–56 (2010).
Zarzhevsky, N. et al. White matter lesions augment cognitive impairments of dopaminergic denervation of the caudate nucleus in Parkinson disease [abstract OP294]. Eur. J. Nucl. Med. Mol. Imaging 37 (Suppl. 2), S249 (2010).
Murrow, R. W., Schweiger, G. D., Kepes, J. J. & Koller, W. C. Parkinsonism due to a basal ganglia lacunar state: clinicopathologic correlation. Neurology 40, 897–900 (1990).
Alexander, G. E., DeLong, M. R. & Strick, P. L. Parallel organization of functionally segregated circuits linking basal ganglia and cortex. Annu. Rev. Neurosci. 9, 357–381 (1986).
Herrmann, L. L., Le Masurier, M. & Ebmeier, K. P. White matter hyperintensities in late life depression: a systematic review. J. Neurol. Neurosurg. Psychiatry 79, 619–624 (2008).
Kerr, B., Condon, S. M. & McDonald, L. A. Cognitive spatial processing and the regulation of posture. J. Exp. Psychol. Hum. Percept. Perform. 11, 617–622 (1985).
Takakusaki, K., Tomita, N. & Yano, M. Substrates for normal gait and pathophysiology of gait disturbances with respect to the basal ganglia dysfunction. J. Neurol. 255 (Suppl. 4), 19–29 (2008).
Critchley, M. Arteriosclerotic parkinsonism. Brain 52, 23–83 (1929).
Kalra, S., Grosset, D. G. & Benamer, H. T. Differentiating vascular parkinsonism from idiopathic Parkinson's disease: a systematic review. Mov. Disord. 25, 149–156 (2010).
Thompson, P. D. & Marsden, C. D. Gait disorder of subcortical arteriosclerotic encephalopathy: Binswanger's disease. Mov. Disord. 2, 1–8 (1987).
Grimbergen, Y. A., Langston, J. W., Roos, R. A. & Bloem, B. R. Postural instability in Parkinson's disease: the adrenergic hypothesis and the locus coeruleus. Expert Rev. Neurother. 9, 279–290 (2009).
Bloem, B. R., Steijns, J. A. & Smits-Engelsman, B. C. An update on falls. Curr. Opin. Neurol. 16, 15–26 (2003).
Bohnen, N. I. et al. History of falls in Parkinson disease is associated with reduced cholinergic activity. Neurology 73, 1670–1676 (2009).
Horak, F. B. Postural orientation and equilibrium: what do we need to know about neural control of balance to prevent falls? Age Ageing 35 (Suppl. 2), ii7–ii11 (2006).
Papapetropoulos, S. et al. The effect of vascular disease on late onset Parkinson's disease. Eur. J. Neurol. 11, 231–235 (2004).
Park, K. et al. Significant association between leukoaraiosis and metabolic syndrome in healthy subjects. Neurology 69, 974–978 (2007).
Nakaso, K. et al. Hypertrophy of IMC of carotid artery in Parkinson's disease is associated with L-DOPA, homocysteine, and MTHFR genotype. J. Neurol. Sci. 207, 19–23 (2003).
Aisen, P. S. et al. High-dose B vitamin supplementation and cognitive decline in Alzheimer disease: a randomized controlled trial. JAMA 300, 1774–1783 (2008).
VITATOPS Trial Study Group. B vitamins in patients with recent transient ischaemic attack or stroke in the VITAmins TO Prevent Stroke (VITATOPS) trial: a randomised, double-blind, parallel, placebo-controlled trial. Lancet Neurol. 9, 855–865 (2010).
Wright, C. B. et al. White matter hyperintensities and subclinical infarction: associations with psychomotor speed and cognitive flexibility. Stroke 39, 800–805 (2008).
Alves, G., Larsen, J. P., Emre, M., Wentzel-Larsen, T. & Aarsland, D. Changes in motor subtype and risk for incident dementia in Parkinson's disease. Mov. Disord. 21, 1123–1130 (2006).
Brickman, A. M. et al. Reduction in cerebral blood flow in areas appearing as white matter hyperintensities on magnetic resonance imaging. Psychiatry Res. 172, 117–120 (2009).
Bastos-Leite, A. J. et al. Cerebral blood flow by using pulsed arterial spin-labeling in elderly subjects with white matter hyperintensities. AJNR Am. J. Neuroradiol. 29, 1296–1301 (2008).
Kuczynski, B. et al. White matter integrity and cortical metabolic associations in aging and dementia. Alzheimers Dement. 6, 54–62 (2010).
Jagust, W. J. et al. Neuropathological basis of magnetic resonance images in aging and dementia. Ann. Neurol. 63, 72–80 (2008).
Schuur, M. et al. Genetic risk factors for cerebral small-vessel disease in hypertensive patients from a genetically isolated population. J. Neurol. Neurosurg. Psychiatry 82, 41–44 (2011).
Lieberman, A. et al. Dementia in Parkinson's disease. Ann. Neurol. 6, 355–359 (1979).
Utter, S. et al. Cerebral small vessel disease-induced apolipoprotein E leakage is associated with Alzheimer disease and the accumulation of amyloid beta-protein in perivascular astrocytes. J. Neuropathol. Exp. Neurol. 67, 842–856 (2008).
Schneider, J. A., Arvanitakis, Z., Leurgans, S. E. & Bennett, D. A. The neuropathology of probable Alzheimer disease and mild cognitive impairment. Ann. Neurol. 66, 200–208 (2009).
Acknowledgements
The authors thank Bryan Benson for his assistance with the MRI figures. The authors gratefully acknowledge research support from the NIH–National Institute of Neurological Disorders and Stroke, the Department of Veterans Affairs and the Michael J. Fox Foundation.
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Bohnen, N., Albin, R. White matter lesions in Parkinson disease. Nat Rev Neurol 7, 229–236 (2011). https://doi.org/10.1038/nrneurol.2011.21
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DOI: https://doi.org/10.1038/nrneurol.2011.21
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