- Email: [email protected]
The aging striatal dopamine function
Parkinsonism and Related Disorders 18 (2012) 426e432
Contents lists available at SciVerse ScienceDirect
Parkinsonism and Related Disorders journal homepage: www.elsevier.com/locate/parkreldis
Review
The aging striatal dopamine function Olivier Darbin a, b, * a b
Department of Neurology, University South Alabama, 307 University Blvd., Mobile, AL 36688, USA Division of System Neurophysiology, National Institute for Physiological Sciences, Okazaki, Japan
a r t i c l e i n f o
a b s t r a c t
Article history: Received 27 August 2011 Received in revised form 23 November 2011 Accepted 27 November 2011
Movement disorders are prevalent in the elderly and may have both central and peripheral origins. Agerelated parkinsonism often results in movement disorders identical to some of the cardinal symptoms of typical Parkinson’s disease (TPD). Nevertheless, there may be limited similarity in the underlying dysfunction of the sensory-motor circuitry since these two conditions exhibit different changes in the nigro-striatal pathway. In this short review, we highlight some of the key distinctions between aging and TPD regarding striatal dopaminergic activity and discuss them in the context of therapeutic strategies to alleviate motor decline in the elderly. Ó 2011 Elsevier Ltd. All rights reserved.
Keywords: Elderly Catecholamine Nigro-striatal pathway Motor activity Dopamine depletion
Contents 1. 2.
3.
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 426 Aging and striatal dopaminergic neurotransmission . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .427 2.1. Striatal dopamine metabolism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 427 2.2. Striatal dopamine receptors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 427 2.3. Age-related response to dopaminergic treatments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 427 2.4. Aged-related striatal dopamine alterations: what are the possible consequences on basal ganglia circuitry activity? . . . . . . . . . . . . . . . . . . . . . 428 2.5. Striatal dopaminergic system, aging and Parkinson’s disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 429 Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 430 Acknowledgment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 430 Full financial disclosure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 430 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 430
1. Introduction Motor signs of parkinsonism increase with aging and affect more than 50% of people over the age of 85 years [1]. They are predictive of lifespan [1e3], contribute to the perception of deterioration in quality of life [4] and have an economical impact. In the elderly, motor symptoms with the highest prevalence include: bradykinesia (37%), gait disturbance (51%) and rigidity (43%) but * Corresponding author. Department of Neurology, University of South Alabama College of Medicine, 3401 Medical Park Dr., Bldg 3, Suite 205, Mobile, AL 36608, USA. Tel.: þ1 770 329 8773; fax: þ1 251 660 5924. E-mail address: [email protected]. 1353-8020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved. doi:10.1016/j.parkreldis.2011.11.025
resting tremor, a cardinal symptom of typical Parkinson’s disease (TPD), has a low prevalence (5%) in the elderly [1]. In contrast to TPD, dopaminergic replacement strategies are ineffective at relieving the burden associated with age-related parkinsonism. Though this lack of benefit may indicate complex and diffuse alterations along the motor efferent pathway [5], it may also be due to the fact that TPD and age-related parkinsonism exhibit different neuropathological hallmarks in the central motor circuitry. Understanding the specificities of age-related parkinsonism, in comparison to TPD, is an important step for efficient cross discipline research between these two conditions. Ultimately, the identification of reversible central dysfunctions in the aging central motor circuitry could facilitate our ability to develop new therapeutic
O. Darbin / Parkinsonism and Related Disorders 18 (2012) 426e432
strategies to reduce the severity of or delay the onset of parkinsonism related to aging. Numerous structural studies have pointed to age-related changes in the basal ganglia. The basal ganglia, as part of the cortico-cortical loops within the sensory-motor circuitry, are involved in the planning, initiation and control of voluntary movement [6e9]. Specifically, dopamine depletion in the major input nucleus of the basal ganglia, e.g. the striatum, is manifested by the inability to initiate and cease movement, the inability to suppress involuntary movement, an abnormality in the velocity and amount of movement, and abnormal muscle tone [9e11]. In typical PD, the depletion in striatal dopamine is considered to be a contributing factor to akinesia which is responsive to dopamine replacement therapy. Markers for striatal dopaminergic activities, such as enzymes [12e15] and receptors [16e19], have consistently been reported as being altered [12,20e24] in the aging basal ganglia. However, Lewy body pathologies and loss of dopaminergic cells in the nigro-striatal pathway, which are hallmarks for TPD (i.e. see Ref. [25]), are not reliable markers for aging [20,23,24]. Agerelated parkinsonism-like symptoms have been identified in experimental animal models [2,26]. Here, we review evidence that age-related alterations in striatal dopamine function are different from those observed in TPD and could contribute, at least partially, to the poor response of age-related parkinsonism to dopamine replacement therapies. 2. Aging and striatal dopaminergic neurotransmission 2.1. Striatal dopamine metabolism Aging results in morphological and neurochemical changes in the basal ganglia that may contribute to the decline in motor, cognitive and affective functions [27e32]. Parkinsonism related to aging may occur without major decrease in the number of nigral dopaminergic cells [23,33e38], and with only moderate degeneration of the nigro-striatal pathway (15e45%) [23,25,26,39e46]. This is an important distinction from TPD for which cardinal motor symptoms occur when nigral dopaminergic cell loss exceeds 80% [47]. When it occurs in the aging brain, dopaminergic cell loss does not correlate in time with the development of motor symptoms. In fact, dopamine cell loss has been shown to be more prevalent in young and adult subjects than middle-aged and old subjects [23]. However, aging results in decreased striatal dopaminergic activity in rodents [24,48e50], monkeys [51], primates [52] and humans [13,14]. Early studies showed decreased levels in dopamine tissue content in the rat striatum [53]. In aged rodents [54e58] and aged non-human primates [59], in-vivo monitoring of the extracellular content of dopamine (and its first metabolite) by microdialysis confirmed decreased base line levels and evoked response to a high potassium challenge. From this, one can infer that dopamine depletion, but not dopaminergic cell loss, is a hallmark for aging and correlates with the occurrence of motor decline [36] (Fig. 1). A decline in synthesis (rather than increased degradation) appears to be the main contributor to age-related dopamine depletion. Clinical studies using positron emission tomography with 11C-labeled L-DOPA have established an age-related decrease in striatal L-DOPA utilization and dopamine synthesis in the striatum of the neurologically normal elderly [21]. This was also confirmed in aged non-human primates that exhibit a reduced increase in striatal dopamine levels following local administration of a DAT inhibitor [16]. In adult mammals, the dopamine synthesis is limited by the activity of tyrosine hydroxylase (TH) [49,60] and LDOPA decarboxylase (DDC, or AADC for aromatic amino acid decarboxylase). In aged subjects, the activity for both TH [12e15]
427
and DDC [16,61,62] is decreased but their relative contribution to the depletion in striatal dopamine remains a matter of debate [12,13] (Fig. 2). In comparison to aging, typical PD is associated with an increased striatal dopaminergic metabolism in the surviving dopaminergic terminals as the loss of DA neurons progresses in the substantia nigra compacta [63,64] (Fig. 2). Aging affects not only the striatal synthesis of dopamine but also the local activity and expression of the dopamine transporter (DAT) [65e72]. At least two mechanisms appear to be involved in age-related decline in striatal DAT function. The first mechanism involves a DAT redistribution away from the plasma membrane [65] consecutive to a deficit in glycosylation [38]. The second mechanism involves a decrease in DAT binding and DAT-mRNA which may be a down regulation in response to the decrease in DA levels [69]. As a consequence of this, it is remarkable that both aging and TPD result in striatal dopamine depletion. However, the origins of the structural and metabolic alterations of this depletion in dopamine differ greatly between these two conditions. 2.2. Striatal dopamine receptors The age-related decrease in striatal dopamine metabolism is also associated with changes in local dopamine receptors. In rodents, monkeys and humans, studies have reported an agerelated decline in the binding of selective agents to either D2[16,17] or D1-dopamine receptors [16e19]. Therefore, the expression for two DA receptor families is reduced in the aged striatum (Fig. 2). This is in contrast to TPD which, in fact, exhibits an increased expression in striatal dopamine D2 receptors (but not D1) [73e76]. Age-related alteration in the striatal dopaminergic terminals includes functional impairments at both pre- and post-synaptic levels. In the next paragraph, we discuss the impact of these alterations on the effects of dopaminergic treatment for age-related motor decline. 2.3. Age-related response to dopaminergic treatments In patients with typical PD and in the first half decade of treatment, brain dopamine replacement is beneficial for some specific motor symptoms including bradykinesia and hypokinesia [77]. In contrast to TPD, clinical studies performed in healthy elderly humans have reported poor or no benefit from dopamine replacement therapy (L-DOPA) on age-related motor decline. In a double-blind crossover study in normal elderly humans, the effects of carbidopa/levodopa have been investigated on movement velocity, reaction time, tremor and visual evoked responses (VER). This treatment was found to have no benefit on both motor functions and VER [78]. More recently, the lack of efficacy of antiparkinsonian dopaminergic medication was also reported on event-related potentials (ERPs) during a stimulus-response (S-R) compatibility task in elderly humans [79]. It is probable that decreased DDC activity in the aged striatum [12] may contribute to a poor neuronal utilization of L-DOPA and the limited benefit of this treatment for age-related motor decline [80e82]. In addition to a weak bio-transformation of L-DOPA, DA may also have a limited action since aging is associated with a decreased expression in striatal post-synaptic DA receptors. In aged rhesus monkeys, systemic administration of apomorphine weakly increases motor activities in comparatively to its effect in young primates [83]. Interestingly, experimental studies in rodents have shown that agerelated decline in motor function is not reversed by D2R gene transfer in the striatum [84], suggesting that other mechanisms, downstream to post-synaptic dopaminergic receptors, may also
428
O. Darbin / Parkinsonism and Related Disorders 18 (2012) 426e432
Fig. 1. Origins of striatal dopamine depletion in TPD (b) and age-related parkinsonism (c) in comparison to normal adult condition (a). A: Normal condition in healthy adult. B: In TPD striatal dopamine depletion results from a dramatic loss in the number of dopaminergic cells in the SNc. C: In age-related parkinsonism, striatal dopamine depletion is mostly explained by a substantial decrease in dopamine synthesize in the nigro-striatal terminals.
contribute to limit the reversal of age-related motor decline by dopaminergic treatments. 2.4. Aged-related striatal dopamine alterations: what are the possible consequences on basal ganglia circuitry activity? Though age-related alterations in striatal dopaminergic activity are expected to result in dysfunction in the basal ganglia, the natures of these changes remain sparsely documented. The current functional model of basal ganglia for movement disorders is founded upon two main assumptions. The first
assumption is that the direct pathway (Str-GPi/SNr) is up regulated by the D1 receptor and the indirect pathway (Str-GPe-GPi/SNr) is down regulated by the D2 receptor. The second assumption is that an imbalance of activity in favor of the direct pathway enhances motor selection (i.e. hyperkinesia) and imbalanced activity in favor of the indirect pathway enhances motor inhibition (i.e. hypokinesia) [85]. In PD, the model predicts that depletion in striatal dopamine can cause a down regulation of the direct pathway and up regulation of the indirect pathway. The resulting imbalance in favor of the indirect pathway is predicted to increase activity in the output nuclei of the basal ganglia (GPi) and, therefore, motor
O. Darbin / Parkinsonism and Related Disorders 18 (2012) 426e432
429
Fig. 2. Age-related changes in striatal dopamine neurotransmission (b) comparative to normal adult condition (a). A: In normal adult, Tyrosine (Tyr) is metabolized in L-DOPA by the Tyrosine Hydroxylase (TH) which is transformed in Dopamine (DA) by the L-DOPA decarboxylase (DDC). Intracellular dopamine ([DA]i) is released by transporter-dependent or exocytotic mechanisms in the extra-cellular space ([DA]e). When in the extra-cellular space, dopamine modulates the medium spiny neurons through D1-like receptors for the direct pathway or through D2-like receptors for the indirect pathway. B: In age-related parkinsonism, expression of both TH and DDC decreases the synthesis of dopamine resulting in striatal dopamine depletion. In addition, and at the post-synaptic levels, the expressions of both D1 and D2 family receptors are reduced.
inhibition [86e89]. Though this model is rigorously debated, it may be used as a reference for discussing basal ganglia dysfunction in regard to movement disorders. In the aging striatum, depletion in both dopamine and dopaminergic receptors has the potential to decrease the D2-mediated inhibition on the indirect pathway and the D1-mediated excitation on the direct pathway. Concerning the model previously cited, it is conceivable that an increased activity in the GPi could contribute to age-related motor decline. A few fMRI studies have attempted to determine age-related changes in basal ganglia activity with a special focus on the output nuclei [90e92]. Previous fMRI studies in the elderly have reported an aging-related increased activity in the GP [93]. Due to technical limitations, the GPe and GPi were not distinguished in this last study and therefore, the study failed to identify the effects of aging specifically on the output nuclei of the basal ganglia (namely the GPi and the SN). In another study, the effects of the D1/D2 agonist apomorphine were specifically investigated on the output nuclei of the basal ganglia [83]. In young non-human primates, systemic administration of apomorphine increases the local measurement of blood oxygen level-dependency (BOLD response) in the GPi and SN [83], a response consistent with a decreased activity in the output nuclei and hyperkinesias, as predicted by the model. In aged primates, the
same pharmacological challenge failed to affect the activities in GPi and SN [83]. This finding reinforces the hypothesis that aging is associated with decreased dopaminergic control of balanced activity between the direct and indirect pathways and therefore failed to report direct evidence for an imbalance between the direct and indirect pathway. From studies on the striatal dopaminergic synapse and the responses of motor decline to dopaminergic treatment, there is an accumulation of evidence that raises questions and controversies about whether aging and PD [52] exhibit similar dysfunctions in the basal ganglia circuitry. 2.5. Striatal dopaminergic system, aging and Parkinson’s disease Experimental studies in primates showed that even in the absence of an overall neuronal loss, changes in the characteristics of dopaminergic cells reflect functional deficits and increased vulnerability to injury with age [23]. In addition, the overall agerelated decrease in striatal dopamine neurotransmission may limit some compensatory responses to the decrement in DA cell loss in PD [94] and therefore, in line with Collier et al. [95], have the potential to decrease the threshold for the expression of parkinsonian symptoms [95,96]. However, Lewy body pathology,
430
O. Darbin / Parkinsonism and Related Disorders 18 (2012) 426e432
hallmarks of PD, is less prevalent [97] than signs for parkinsonism [1] in the elderly population. Therefore, there is neither evidence to support age-dependent neurodegenerative processes as primary causes of TPD [14], nor to associate automatically, age-related parkinsonism to early stage TPD. Nevertheless, age-related parkinsonism likely contributes to age-dependent occurrences of complications in patients with TPD [96] such as changes in clinical symptoms [98] and response to treatments [99,100]. 3. Conclusion Normal aging is associated with circuitry alterations in the basal ganglia. The effects of aging on the striatal dopaminergic synapse differ from those resulting from TPD. The specific effects of aging on dopaminergic neurotransmission in the striatum likely contribute to both age-related parkinsonism and the poor improvement in mobility with dopaminergic treatment. These differences raise questions about whether age-related parkinsonism and TPD share similar basal ganglia dysfunctions. It is expected that the identification of electrophysiological hallmarks of aging in the basal ganglia will aid in developing a functional model of the aging motor circuitry. The extent of age-related dysfunction at the level of the striatal dopaminergic synapse suggests a shift of focus toward nondopaminergic anti-parkinsonian medications [101] and more comparisons with atypical parkinsonian conditions. Ultimately, identification of treatments that alleviate age-related parkinsonism may also benefit the long-term management of aging patients with TPD. Acknowledgment Dr O. Darbin is principally supported by the Department of Neurology University of South Alabama College of Medicine, Mobile, AL and by the Division of System Neurophysiology at the National Institute of Japan for Physiological Sciences (NIJPS-Okasaki). The author would like to thank Dr D.E. Salter and Susan Calne for the editing of the manuscript. This manuscript is dedicated to the memory of Pr R. Joly. Full financial disclosure Nothing to report. References [1] Bennett DA, Beckett LA, Murray AM, Shannon KM, Goetz CG, Pilgrim DM, et al. Prevalence of parkinsonian signs and associated mortality in a community population of older people. N Engl J Med 1996;334:71e6. [2] Ingram DK. Age-related decline in physical activity: generalization to nonhumans. Med Sci Sports Exerc 2000;32:1623e9. [3] Wilson RS, Schneider JA, Beckett LA, Evans DA, Bennett DA. Progression of gait disorder and rigidity and risk of death in older persons. Neurology 2002; 58:1815e9. [4] Larsson L, Ramamurthy B. Aging-related changes in skeletal muscle. Mechanisms and interventions. Drugs Aging 2000;17:303e16. [5] Dickstein DL, Kabaso D, Rocher AB, Luebke JI, Wearne SL, Hof PR. Changes in the structural complexity of the aged brain. Aging Cell 2007;6:275e84. [6] Middleton FA, Strick PL. Basal ganglia and cerebellar loops: motor and cognitive circuits. Brain Res Brain Res Rev 2000;31:236e50. [7] Alexander GE, Crutcher MD. Functional architecture of basal ganglia circuits: neural substrates of parallel processing. Trends Neurosci 1990;13:266e71. [8] Delong MR. Primate models of movement-disorders of basal ganglia origin. Trends Neurosci 1990;13:281e5. [9] Turner RS, Grafton ST, Votaw JR, Delong MR, Hoffman JM. Motor subcircuits mediating the control of movement velocity: a PET study. J Neurophysiol 1998;80:2162e76. [10] Obeso JA, Rodriguez MC, DeLong MR. Basal ganglia pathophysiology. A critical review. Adv Neurol 1997;74:3e18. [11] Saint-Cyr JA. Basal ganglia: functional perspectives and behavioral domains. Adv Neurol 2005;96:1e16.
[12] Cruz-Muros I, Afonso-Oramas D, Abreu P, Barroso-Chinea P, Rodriguez M, Gonzalez MC, et al. Aging of the rat mesostriatal system: differences between the nigrostriatal and the mesolimbic compartments. Exp Neurol 2007;204: 147e61. [13] Haycock JW, Becker L, Ang L, Furukawa Y, Hornykiewicz O, Kish SJ. Marked disparity between age-related changes in dopamine and other presynaptic dopaminergic markers in human striatum. J Neurochem 2003;87:574e85. [14] Kish SJ, Shannak K, Rajput A, Deck JH, Hornykiewicz O. Aging produces a specific pattern of striatal dopamine loss: implications for the etiology of idiopathic Parkinson’s disease. J Neurochem 1992;58:642e8. [15] Lloyd KG, Hornykiewicz O. Occurrence and distribution of aromatic L-amino acid (L-DOPA) decarboxylase in the human brain. J Neurochem 1972;19: 1549e59. [16] Harada N, Nishiyama S, Satoh K, Fukumoto D, Kakiuchi T, Tsukada H. Agerelated changes in the striatal dopaminergic system in the living brain: a multiparametric PET study in conscious monkeys. Synapse 2002;45:38e45. [17] Suzuki M, Hatano K, Sakiyama Y, Kawasumi Y, Kato T, Ito K. Age-related changes of dopamine D1-like and D2-like receptor binding in the F344/N rat striatum revealed by positron emission tomography and in vitro receptor autoradiography. Synapse 2001;41:285e93. [18] Wang Y, Chan GL, Holden JE, Dobko T, Mak E, Schulzer M, et al. Agedependent decline of dopamine D1 receptors in human brain: a PET study. Synapse 1998;30:56e61. [19] Giorgi O, De Montis G, Porceddu ML, Mele S, Calderini G, Toffano G, et al. Developmental and age-related changes in D1-dopamine receptors and dopamine content in the rat striatum. Brain Res 1987;432:283e90. [20] Stark AK, Pakkenberg B. Histological changes of the dopaminergic nigrostriatal system in aging. Cell Tissue Res 2004;318:81e92. [21] Ota M, Yasuno F, Ito H, Seki C, Nozaki S, Asada T, et al. Age-related decline of dopamine synthesis in the living human brain measured by positron emission tomography with L-[beta-11C]DOPA. Life Sci 2006;79:730e6. [22] Ishida Y, Okawa Y, Ito S, Shirokawa T, Isobe K. Age-dependent changes in dopaminergic projections from the substantia nigra pars compacta to the neostriatum. Neurosci Lett 2007;418:257e61. [23] McCormack AL, Di Monte DA, Delfani K, Irwin I, DeLanney LE, Langston WJ, et al. Aging of the nigrostriatal system in the squirrel monkey. J Comp Neurol 2004;471:387e95. [24] Colebrooke RE, Humby T, Lynch PJ, McGowan DP, Xia J, Emson PC. Agerelated decline in striatal dopamine content and motor performance occurs in the absence of nigral cell loss in a genetic mouse model of Parkinson’s disease. Eur J Neurosci 2006;24:2622e30. [25] Fearnley JM, Lees AJ. Ageing and Parkinson’s disease: substantia nigra regional selectivity. Brain 1991;114(Pt 5):2283e301. [26] Emborg ME, Ma SY, Mufson EJ, Levey AI, Taylor MD, Brown WD, et al. Agerelated declines in nigral neuronal function correlate with motor impairments in rhesus monkeys. J Comp Neurol 1998;401:253e65. [27] Barili P, De Carolis G, Zaccheo D, Amenta F. Sensitivity to ageing of the limbic dopaminergic system: a review. Mech Ageing Dev 1998;106:57e92. [28] Reeves S, Bench C, Howard R. Ageing and the nigrostriatal dopaminergic system. Int J Geriatr Psychiatry 2002;17:359e70. [29] Smith CD, Chebrolu H, Wekstein DR, Schmitt FA, Markesbery WR. Age and gender effects on human brain anatomy: a voxel-based morphometric study in healthy elderly. Neurobiol Aging 2007;28:1075e87. [30] Gunning-Dixon FM, Head D, McQuain J, Acker JD, Raz N. Differential aging of the human striatum: a prospective MR imaging study. AJNR Am J Neuroradiol 1998;19:1501e7. [31] Good CD, Johnsrude IS, Ashburner J, Henson RN, Friston KJ, Frackowiak RS. A voxel-based morphometric study of ageing in 465 normal adult human brains. Neuroimage 2001;14:21e36. [32] Raz N, Gunning-Dixon FM, Head D, Dupuis JH, Acker JD. Neuroanatomical correlates of cognitive aging: evidence from structural magnetic resonance imaging. Neuropsychology 1998;12:95e114. [33] Pakkenberg H, Andersen BB, Burns RS, Pakkenberg B. A stereological study of substantia nigra in young and old rhesus monkeys. Brain Res 1995;693:201e6. [34] Kubis N, Faucheux BA, Ransmayr G, Damier P, Duyckaerts C, Henin D, et al. Preservation of midbrain catecholaminergic neurons in very old human subjects. Brain 2000;123:366e73. [35] McNeill TH, Koek LL. Differential effects of advancing age on neurotransmitter cell loss in the substantia nigra and striatum of C57BL/6N mice. Brain Res 1990;521:107e17. [36] Emerich DF, McDermott P, Krueger P, Banks M, Zhao J, Marszalkowski J, et al. Locomotion of aged rats: relationship to neurochemical but not morphological changes in nigrostriatal dopaminergic neurons. Brain Res Bull 1993; 32:477e86. [37] Irwin I, DeLanney LE, McNeill T, Chan P, Forno LS, Murphy Jr GM, et al. Aging and the nigrostriatal dopamine system: a non-human primate study. Neurodegeneration 1994;3:251e65. [38] Salvatore MF, Apparsundaram S, Gerhardt GA. Decreased plasma membrane expression of striatal dopamine transporter in aging. Neurobiol Aging 2003; 24:1147e54. [39] McGeer PL, McGeer EG, Suzuki JS. Aging and extrapyramidal function. Arch Neurol 1977;34:33e5. [40] Mann DM, Yates PO. The effects of ageing on the pigmented nerve cells of the human locus caeruleous and substantia nigra. Acta Neuropathol 1979;47:93e7.
O. Darbin / Parkinsonism and Related Disorders 18 (2012) 426e432 [41] Thiessen B, Rajput AH, Laverty W, Desai H. Age, environments, and the number of substantia nigra neurons. Adv Neurol 1990;53:201e6. [42] Ma SY, Roytt M, Collan Y, Rinne JO. Unbiased morphometrical measurements show loss of pigmented nigral neurones with ageing. Neuropathol Appl Neurobiol 1999;25:394e9. [43] Siddiqi Z, Kemper TL, Killiany R. Age-related neuronal loss from the substantia nigra-pars compacta and ventral tegmental area of the rhesus monkey. J Neuropathol Exp Neurol 1999;58:959e71. [44] Cabello CR, Thune JJ, Pakkenberg H, Pakkenberg B. Ageing of substantia nigra in humans: cell loss may be compensated by hypertrophy. Neuropathol Appl Neurobiol 2002;28:283e91. [45] Chu Y, Kompoliti K, Cochran EJ, Mufson EJ, Kordower JH. Age-related decreases in Nurr1 immunoreactivity in the human substantia nigra. J Comp Neurol 2002;450:203e14. [46] Vaillancourt DE, Spraker MB, Prodoehl J, Zhou XJ, Little DM. Effects of aging on the ventral and dorsal substantia nigra using diffusion tensor imaging. Neurobiol Aging; 2010. [47] Bernheimer H, Birkmayer W, Hornykiewicz O, Jellinger K, Seitelberger F. Brain dopamine and the syndromes of Parkinson and Huntington. J Neurol Sci 1973;20:415e55. [48] Miguez JM, Aldegunde M, Paz-Valinas L, Recio J, Sanchez-Barcelo E. Selective changes in the contents of noradrenaline, dopamine and serotonin in rat brain areas during aging. J Neural Transm 1999;106:1089e98. [49] Udenfriend S. Tyrosine hydroxylase. Pharmacol Rev 1966;18:43e51. [50] Yurek DM, Hipkens SB, Hebert MA, Gash DM, Gerhardt GA. Age-related decline in striatal dopamine release and motoric function in brown Norway/ Fischer 344 hybrid rats. Brain Res 1998;791:246e56. [51] Gerhardt GA, Cass WA, Yi A, Zhang Z, Gash DM. Changes in somatodendritic but not terminal dopamine regulation in aged rhesus monkeys. J Neurochem 2002;80:168e77. [52] Hurley PJ, Elsworth JD, Whittaker MC, Roth RH, Redmond Jr DE. Aged monkeys as a partial model for Parkinson’s disease. Pharmacol Biochem Behav 2011;99:324e32. [53] Gozlan H, Daval G, Verge D, Spampinato U, Fattaccini CM, Gallissot MC, et al. Aging associated changes in serotoninergic and dopaminergic pre- and postsynaptic neurochemical markers in the rat brain. Neurobiol Aging 1990; 11:437e49. [54] Dluzen DE, McDermott JL, Ramirez VD. Changes in dopamine release in vitro from the corpus striatum of young versus aged rats as a function of infusion modes of L-dopa, potassium, and amphetamine. Exp Neurol 1991;112: 153e60. [55] Joseph JA, Dalton TK, Hunt WA. Age-related decrements in the muscarinic enhancement of Kþ-evoked release of endogenous striatal dopamine: an indicator of altered cholinergic-dopaminergic reciprocal inhibitory control in senescence. Brain Res 1988;454:140e8. [56] Nakano M, Mizuno T. Age-related changes in the metabolism of neurotransmitters in rat striatum: a microdialysis study. Mech Ageing Dev 1996; 86:95e104. [57] Rose GM, Gerhardt GA, Conboy GL, Hoffer BJ. Age-related alterations in monoamine release from rat striatum: an in vivo electrochemical study. Neurobiol Aging 1986;7:77e82. [58] Santiago M, Machado A, Cano J. Effects of age and dopamine agonists and antagonists on striatal dopamine release in the rat: an in vivo microdialysis study. Mech Ageing Dev 1993;67:261e7. [59] Gerhardt GA, Cass WA, Henson M, Zhang Z, Ovadia A, Hoffer BJ, et al. Agerelated changes in potassium-evoked overflow of dopamine in the striatum of the Rhesus monkey. Neurobiol Aging 1995;16:939e46. [60] Levitt M, Spector S, Sjoerdsma A, Udenfriend S. Elucidation of the ratelimiting step in norepinephrine biosynthesis in the perfused guinea-pig heart. J Pharmacol Exp Ther 1965;148:1e8. [61] Martin WRW, Palmer MR, Patlak CS, Calne DB. Nigrostriatal function in humans studied with positron emission tomography. Ann Neurol 1989;26: 535e42. [62] Cordes M, Snow BJ, Cooper S, Schulzer M, Pate BD, Ruth TJ, et al. Agedependent decline of nigrostriatal dopaminergic function: a positron emission tomographic study of grandparents and their grandchildren. Ann Neurol 1994;36:667e70. [63] Sossi V, de la Fuente-Fernandez R, Schulzer M, Troiano AR, Ruth TJ, Stoessl AJ. Dopamine transporter relation to dopamine turnover in Parkinson’s disease: a positron emission tomography study. Ann Neurol 2007;62:468e74. [64] Biju G, de la Fuente-Fernandez R. Dopaminergic function and progression of Parkinson’s disease: PET findings. Parkinsonism Relat Disord 2009;15(Suppl. 4):S38e40. [65] Hebert MA, Larson GA, Zahniser NR, Gerhardt GA. Age-related reductions in [3H]WIN 35,428 binding to the dopamine transporter in nigrostriatal and mesolimbic brain regions of the fischer 344 rat. J Pharmacol Exp Ther 1999; 288:1334e9. [66] Shimizu I, Prasad C. Relationship between [3H]mazindol binding to dopamine uptake sites and [3H]dopamine uptake in rat striatum during aging. J Neurochem 1991;56:575e9. [67] Erixon-Lindroth N, Farde L, Wahlin TB, Sovago J, Halldin C, Backman L. The role of the striatal dopamine transporter in cognitive aging. Psychiatry Res 2005;138:1e12. [68] van Dyck CH, Seibyl JP, Malison RT, Laruelle M, Zoghbi SS, Baldwin RM, et al. Age-related decline in dopamine transporters: analysis of striatal subregions,
[69]
[70]
[71]
[72]
[73]
[74]
[75]
[76]
[77]
[78]
[79]
[80] [81]
[82] [83]
[84]
[85] [86] [87] [88]
[89]
[90] [91]
[92]
[93]
[94]
[95]
431
nonlinear effects, and hemispheric asymmetries. Am J Geriatr Psychiatry 2002;10:36e43. Cruz-Muros I, Afonso-Oramas D, Abreu P, Perez-Delgado MM, Rodriguez M, Gonzalez-Hernandez T. Aging effects on the dopamine transporter expression and compensatory mechanisms. Neurobiol Aging; 2007. Mozley LH, Gur RC, Mozley PD, Gur RE. Striatal dopamine transporters and cognitive functioning in healthy men and women. Am J Psychiatry 2001;158: 1492e9. Friedemann MN, Gerhardt GA. Regional effects of aging on dopaminergic function in the Fischer-344 rat. Neurobiol Aging 1992;13: 325e32. Hebert MA, Gerhardt GA. Age-related changes in the capacity, rate, and modulation of dopamine uptake within the striatum and nucleus accumbens of Fischer 344 rats: an in vivo electrochemical study. J Pharmacol Exp Ther 1999;288:879e87. Elsworth JD, Brittan MS, Taylor JR, Sladek Jr JR, Redmond Jr DE, Innis RB, et al. Upregulation of striatal D2 receptors in the MPTP-treated vervet monkey is reversed by grafts of fetal ventral mesencephalon: an autoradiographic study. Brain Res 1998;795:55e62. Morissette M, Goulet M, Calon F, Falardeau P, Blanchet PJ, Bedard PJ, et al. Changes of D1 and D2 dopamine receptor mRNA in the brains of monkeys lesioned with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine: correction with chronic administration of L-3,4-dihydroxyphenylalanine. Mol Pharmacol 1996;50:1073e9. Rinne JO, Laihinen A, Ruottinen H, Ruotsalainen U, Nagren K, Lehikoinen P, et al. Increased density of dopamine D2 receptors in the putamen, but not in the caudate nucleus in early Parkinson’s disease: a PET study with [11C] raclopride. J Neurol Sci 1995;132:156e61. Gagnon C, Gomez-Mancilla B, Markstein R, Bedard PJ, Di Paolo T. Effect of adding the D-1 agonist CY 208-243 to chronic bromocriptine treatment of MPTP-monkeys: regional changes of brain dopamine receptors. Prog Neuropsychopharmacol Biol Psychiatry 1995;19:667e76. Yokochi M. Reevaluation of levodopa therapy for the treatment of advanced Parkinson’s disease. Parkinsonism Relat Disord 2009;15(Suppl. 1):S25e30. Newman RP, LeWitt PA, Jaffe M, Calne DB, Larsen TA. Motor function in the normal aging population: treatment with levodopa. Neurology 1985;35: 571e3. Willemssen R, Falkenstein M, Schwarz M, Muller T, Beste C. Effects of aging, Parkinson’s disease, and dopaminergic medication on response selection and control. Neurobiol Aging 2011;32:327e35. White NJ, Barnes TR. Senile parkinsonism, a study of current treatment. Age Ageing 1981;10:81e6. Diederich NJ, Moore CG, Leurgans SE, Chmura TA, Goetz CG. Parkinson disease with old-age onset: a comparative study with subjects with middleage onset. Arch Neurol 2003;60:529e33. Frank C, Pari G, Rossiter JP. Approach to diagnosis of Parkinson disease. Can Fam Physician 2006;52:862e8. Zhang Z, Andersen A, Grondin R, Barber T, Avison R, Gerhardt G, et al. Pharmacological MRI mapping of age-associated changes in basal ganglia circuitry of awake Rhesus monkeys. NeuroImage 2001;14:1159e67. Ingram DK, Ikari H, Umegaki H, Chernak JM, Roth GS. Application of gene therapy to treat age-related loss of dopamine D2 receptor. Exp Gerontol 1998;33:793e804. Gerfen CR, Surmeier DJ. Modulation of striatal projection systems by dopamine. Annu Rev Neurosci; 2010. Galvan A, Wichmann T. Pathophysiology of parkinsonism. Clin Neurophysiol 2008;119:1459e74. Nambu A. A new dynamic model of the cortico-basal ganglia loop. Prog Brain Res 2004;143:461e6. Obeso JA, Marin C, Rodriguez-Oroz C, Blesa J, Benitez-Temino B, MenaSegovia J, et al. The basal ganglia in Parkinson’s disease: current concepts and unexplained observations. Ann Neurol 2008;64(Suppl. 2):S30e46. Tang JK, Moro E, Mahant N, Hutchison WD, Lang AE, Lozano AM, et al. Neuronal firing rates and patterns in the globus pallidus internus of patients with cervical dystonia differ from those with Parkinson’s disease. J Neurophysiol 2007;98:720e9. Ward NS, Frackowiak RS. Age-related changes in the neural correlates of motor performance. Brain 2003;126:873e88. Mattay VS, Fera F, Tessitore A, Hariri AR, Das S, Callicott JH, et al. Neurophysiological correlates of age-related changes in human motor function. Neurology 2002;58:630e5. Calautti C, Serrati C, Baron JC. Effects of age on brain activation during auditory-cued thumb-to-index opposition: a positron emission tomography study. Stroke 2001;32:139e46. Wu T, Zang Y, Wang L, Long X, Li K, Chan P. Normal aging decreases regional homogeneity of the motor areas in the resting state. Neurosci Lett 2007;423: 189e93. Ohashi S, Mori A, Kurihara N, Mitsumoto Y, Nakai M. Age-related severity of dopaminergic neurodegeneration to MPTP neurotoxicity causes motor dysfunction in C57BL/6 mice. Neurosci Lett 2006;401:183e7. Collier TJ, Lipton J, Daley BF, Palfi S, Chu Y, Sortwell C, et al. Aging-related changes in the nigrostriatal dopamine system and the response to MPTP in nonhuman primates: diminished compensatory mechanisms as a prelude to parkinsonism. Neurobiol Dis 2007;26:56e65.
432
O. Darbin / Parkinsonism and Related Disorders 18 (2012) 426e432
[96] Adler CH, Hentz JG, Joyce JN, Beach T, Caviness JN. Motor impairment in normal aging, clinically possible Parkinson’s disease, and clinically probable Parkinson’s disease: longitudinal evaluation of a cohort of prospective brain donors. Parkinsonism Relat Disord 2002;9:103e10. [97] Markesbery WR, Jicha GA, Liu H, Schmitt FA. Lewy body pathology in normal elderly subjects. J Neuropathol Exp Neurol 2009;68:816e22. [98] Kostic V, Przedborski S, Flaster E, Sternic N. Early development of levodopainduced dyskinesias and response fluctuations in young-onset Parkinson’s disease. Neurology 1991;41:202e5.
[99] Sossi V, de la Fuente-Fernandez R, Schulzer M, Adams J, Stoessl AJ. Agerelated differences in levodopa dynamics in Parkinson’s: implications for motor complications. Brain 2006;129:1050e8. [100] Nagayama H, Ueda M, Kumagai T, Tsukamoto K, Nishiyama Y, Nishimura S, et al. Influence of ageing on the pharmacokinetics of levodopa in elderly patients with Parkinson’s disease. Parkinsonism Relat Disord 2011;17:150e2. [101] Emborg ME, Moirano J, Raschke J, Bondarenko V, Zufferey R, Peng S, et al. Response of aged parkinsonian monkeys to in vivo gene transfer of GDNF. Neurobiol Dis 2009;36:303e11.
Contents lists available at SciVerse ScienceDirect
Parkinsonism and Related Disorders journal homepage: www.elsevier.com/locate/parkreldis
Review
The aging striatal dopamine function Olivier Darbin a, b, * a b
Department of Neurology, University South Alabama, 307 University Blvd., Mobile, AL 36688, USA Division of System Neurophysiology, National Institute for Physiological Sciences, Okazaki, Japan
a r t i c l e i n f o
a b s t r a c t
Article history: Received 27 August 2011 Received in revised form 23 November 2011 Accepted 27 November 2011
Movement disorders are prevalent in the elderly and may have both central and peripheral origins. Agerelated parkinsonism often results in movement disorders identical to some of the cardinal symptoms of typical Parkinson’s disease (TPD). Nevertheless, there may be limited similarity in the underlying dysfunction of the sensory-motor circuitry since these two conditions exhibit different changes in the nigro-striatal pathway. In this short review, we highlight some of the key distinctions between aging and TPD regarding striatal dopaminergic activity and discuss them in the context of therapeutic strategies to alleviate motor decline in the elderly. Ó 2011 Elsevier Ltd. All rights reserved.
Keywords: Elderly Catecholamine Nigro-striatal pathway Motor activity Dopamine depletion
Contents 1. 2.
3.
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 426 Aging and striatal dopaminergic neurotransmission . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .427 2.1. Striatal dopamine metabolism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 427 2.2. Striatal dopamine receptors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 427 2.3. Age-related response to dopaminergic treatments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 427 2.4. Aged-related striatal dopamine alterations: what are the possible consequences on basal ganglia circuitry activity? . . . . . . . . . . . . . . . . . . . . . 428 2.5. Striatal dopaminergic system, aging and Parkinson’s disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 429 Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 430 Acknowledgment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 430 Full financial disclosure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 430 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 430
1. Introduction Motor signs of parkinsonism increase with aging and affect more than 50% of people over the age of 85 years [1]. They are predictive of lifespan [1e3], contribute to the perception of deterioration in quality of life [4] and have an economical impact. In the elderly, motor symptoms with the highest prevalence include: bradykinesia (37%), gait disturbance (51%) and rigidity (43%) but * Corresponding author. Department of Neurology, University of South Alabama College of Medicine, 3401 Medical Park Dr., Bldg 3, Suite 205, Mobile, AL 36608, USA. Tel.: þ1 770 329 8773; fax: þ1 251 660 5924. E-mail address: [email protected]. 1353-8020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved. doi:10.1016/j.parkreldis.2011.11.025
resting tremor, a cardinal symptom of typical Parkinson’s disease (TPD), has a low prevalence (5%) in the elderly [1]. In contrast to TPD, dopaminergic replacement strategies are ineffective at relieving the burden associated with age-related parkinsonism. Though this lack of benefit may indicate complex and diffuse alterations along the motor efferent pathway [5], it may also be due to the fact that TPD and age-related parkinsonism exhibit different neuropathological hallmarks in the central motor circuitry. Understanding the specificities of age-related parkinsonism, in comparison to TPD, is an important step for efficient cross discipline research between these two conditions. Ultimately, the identification of reversible central dysfunctions in the aging central motor circuitry could facilitate our ability to develop new therapeutic
O. Darbin / Parkinsonism and Related Disorders 18 (2012) 426e432
strategies to reduce the severity of or delay the onset of parkinsonism related to aging. Numerous structural studies have pointed to age-related changes in the basal ganglia. The basal ganglia, as part of the cortico-cortical loops within the sensory-motor circuitry, are involved in the planning, initiation and control of voluntary movement [6e9]. Specifically, dopamine depletion in the major input nucleus of the basal ganglia, e.g. the striatum, is manifested by the inability to initiate and cease movement, the inability to suppress involuntary movement, an abnormality in the velocity and amount of movement, and abnormal muscle tone [9e11]. In typical PD, the depletion in striatal dopamine is considered to be a contributing factor to akinesia which is responsive to dopamine replacement therapy. Markers for striatal dopaminergic activities, such as enzymes [12e15] and receptors [16e19], have consistently been reported as being altered [12,20e24] in the aging basal ganglia. However, Lewy body pathologies and loss of dopaminergic cells in the nigro-striatal pathway, which are hallmarks for TPD (i.e. see Ref. [25]), are not reliable markers for aging [20,23,24]. Agerelated parkinsonism-like symptoms have been identified in experimental animal models [2,26]. Here, we review evidence that age-related alterations in striatal dopamine function are different from those observed in TPD and could contribute, at least partially, to the poor response of age-related parkinsonism to dopamine replacement therapies. 2. Aging and striatal dopaminergic neurotransmission 2.1. Striatal dopamine metabolism Aging results in morphological and neurochemical changes in the basal ganglia that may contribute to the decline in motor, cognitive and affective functions [27e32]. Parkinsonism related to aging may occur without major decrease in the number of nigral dopaminergic cells [23,33e38], and with only moderate degeneration of the nigro-striatal pathway (15e45%) [23,25,26,39e46]. This is an important distinction from TPD for which cardinal motor symptoms occur when nigral dopaminergic cell loss exceeds 80% [47]. When it occurs in the aging brain, dopaminergic cell loss does not correlate in time with the development of motor symptoms. In fact, dopamine cell loss has been shown to be more prevalent in young and adult subjects than middle-aged and old subjects [23]. However, aging results in decreased striatal dopaminergic activity in rodents [24,48e50], monkeys [51], primates [52] and humans [13,14]. Early studies showed decreased levels in dopamine tissue content in the rat striatum [53]. In aged rodents [54e58] and aged non-human primates [59], in-vivo monitoring of the extracellular content of dopamine (and its first metabolite) by microdialysis confirmed decreased base line levels and evoked response to a high potassium challenge. From this, one can infer that dopamine depletion, but not dopaminergic cell loss, is a hallmark for aging and correlates with the occurrence of motor decline [36] (Fig. 1). A decline in synthesis (rather than increased degradation) appears to be the main contributor to age-related dopamine depletion. Clinical studies using positron emission tomography with 11C-labeled L-DOPA have established an age-related decrease in striatal L-DOPA utilization and dopamine synthesis in the striatum of the neurologically normal elderly [21]. This was also confirmed in aged non-human primates that exhibit a reduced increase in striatal dopamine levels following local administration of a DAT inhibitor [16]. In adult mammals, the dopamine synthesis is limited by the activity of tyrosine hydroxylase (TH) [49,60] and LDOPA decarboxylase (DDC, or AADC for aromatic amino acid decarboxylase). In aged subjects, the activity for both TH [12e15]
427
and DDC [16,61,62] is decreased but their relative contribution to the depletion in striatal dopamine remains a matter of debate [12,13] (Fig. 2). In comparison to aging, typical PD is associated with an increased striatal dopaminergic metabolism in the surviving dopaminergic terminals as the loss of DA neurons progresses in the substantia nigra compacta [63,64] (Fig. 2). Aging affects not only the striatal synthesis of dopamine but also the local activity and expression of the dopamine transporter (DAT) [65e72]. At least two mechanisms appear to be involved in age-related decline in striatal DAT function. The first mechanism involves a DAT redistribution away from the plasma membrane [65] consecutive to a deficit in glycosylation [38]. The second mechanism involves a decrease in DAT binding and DAT-mRNA which may be a down regulation in response to the decrease in DA levels [69]. As a consequence of this, it is remarkable that both aging and TPD result in striatal dopamine depletion. However, the origins of the structural and metabolic alterations of this depletion in dopamine differ greatly between these two conditions. 2.2. Striatal dopamine receptors The age-related decrease in striatal dopamine metabolism is also associated with changes in local dopamine receptors. In rodents, monkeys and humans, studies have reported an agerelated decline in the binding of selective agents to either D2[16,17] or D1-dopamine receptors [16e19]. Therefore, the expression for two DA receptor families is reduced in the aged striatum (Fig. 2). This is in contrast to TPD which, in fact, exhibits an increased expression in striatal dopamine D2 receptors (but not D1) [73e76]. Age-related alteration in the striatal dopaminergic terminals includes functional impairments at both pre- and post-synaptic levels. In the next paragraph, we discuss the impact of these alterations on the effects of dopaminergic treatment for age-related motor decline. 2.3. Age-related response to dopaminergic treatments In patients with typical PD and in the first half decade of treatment, brain dopamine replacement is beneficial for some specific motor symptoms including bradykinesia and hypokinesia [77]. In contrast to TPD, clinical studies performed in healthy elderly humans have reported poor or no benefit from dopamine replacement therapy (L-DOPA) on age-related motor decline. In a double-blind crossover study in normal elderly humans, the effects of carbidopa/levodopa have been investigated on movement velocity, reaction time, tremor and visual evoked responses (VER). This treatment was found to have no benefit on both motor functions and VER [78]. More recently, the lack of efficacy of antiparkinsonian dopaminergic medication was also reported on event-related potentials (ERPs) during a stimulus-response (S-R) compatibility task in elderly humans [79]. It is probable that decreased DDC activity in the aged striatum [12] may contribute to a poor neuronal utilization of L-DOPA and the limited benefit of this treatment for age-related motor decline [80e82]. In addition to a weak bio-transformation of L-DOPA, DA may also have a limited action since aging is associated with a decreased expression in striatal post-synaptic DA receptors. In aged rhesus monkeys, systemic administration of apomorphine weakly increases motor activities in comparatively to its effect in young primates [83]. Interestingly, experimental studies in rodents have shown that agerelated decline in motor function is not reversed by D2R gene transfer in the striatum [84], suggesting that other mechanisms, downstream to post-synaptic dopaminergic receptors, may also
428
O. Darbin / Parkinsonism and Related Disorders 18 (2012) 426e432
Fig. 1. Origins of striatal dopamine depletion in TPD (b) and age-related parkinsonism (c) in comparison to normal adult condition (a). A: Normal condition in healthy adult. B: In TPD striatal dopamine depletion results from a dramatic loss in the number of dopaminergic cells in the SNc. C: In age-related parkinsonism, striatal dopamine depletion is mostly explained by a substantial decrease in dopamine synthesize in the nigro-striatal terminals.
contribute to limit the reversal of age-related motor decline by dopaminergic treatments. 2.4. Aged-related striatal dopamine alterations: what are the possible consequences on basal ganglia circuitry activity? Though age-related alterations in striatal dopaminergic activity are expected to result in dysfunction in the basal ganglia, the natures of these changes remain sparsely documented. The current functional model of basal ganglia for movement disorders is founded upon two main assumptions. The first
assumption is that the direct pathway (Str-GPi/SNr) is up regulated by the D1 receptor and the indirect pathway (Str-GPe-GPi/SNr) is down regulated by the D2 receptor. The second assumption is that an imbalance of activity in favor of the direct pathway enhances motor selection (i.e. hyperkinesia) and imbalanced activity in favor of the indirect pathway enhances motor inhibition (i.e. hypokinesia) [85]. In PD, the model predicts that depletion in striatal dopamine can cause a down regulation of the direct pathway and up regulation of the indirect pathway. The resulting imbalance in favor of the indirect pathway is predicted to increase activity in the output nuclei of the basal ganglia (GPi) and, therefore, motor
O. Darbin / Parkinsonism and Related Disorders 18 (2012) 426e432
429
Fig. 2. Age-related changes in striatal dopamine neurotransmission (b) comparative to normal adult condition (a). A: In normal adult, Tyrosine (Tyr) is metabolized in L-DOPA by the Tyrosine Hydroxylase (TH) which is transformed in Dopamine (DA) by the L-DOPA decarboxylase (DDC). Intracellular dopamine ([DA]i) is released by transporter-dependent or exocytotic mechanisms in the extra-cellular space ([DA]e). When in the extra-cellular space, dopamine modulates the medium spiny neurons through D1-like receptors for the direct pathway or through D2-like receptors for the indirect pathway. B: In age-related parkinsonism, expression of both TH and DDC decreases the synthesis of dopamine resulting in striatal dopamine depletion. In addition, and at the post-synaptic levels, the expressions of both D1 and D2 family receptors are reduced.
inhibition [86e89]. Though this model is rigorously debated, it may be used as a reference for discussing basal ganglia dysfunction in regard to movement disorders. In the aging striatum, depletion in both dopamine and dopaminergic receptors has the potential to decrease the D2-mediated inhibition on the indirect pathway and the D1-mediated excitation on the direct pathway. Concerning the model previously cited, it is conceivable that an increased activity in the GPi could contribute to age-related motor decline. A few fMRI studies have attempted to determine age-related changes in basal ganglia activity with a special focus on the output nuclei [90e92]. Previous fMRI studies in the elderly have reported an aging-related increased activity in the GP [93]. Due to technical limitations, the GPe and GPi were not distinguished in this last study and therefore, the study failed to identify the effects of aging specifically on the output nuclei of the basal ganglia (namely the GPi and the SN). In another study, the effects of the D1/D2 agonist apomorphine were specifically investigated on the output nuclei of the basal ganglia [83]. In young non-human primates, systemic administration of apomorphine increases the local measurement of blood oxygen level-dependency (BOLD response) in the GPi and SN [83], a response consistent with a decreased activity in the output nuclei and hyperkinesias, as predicted by the model. In aged primates, the
same pharmacological challenge failed to affect the activities in GPi and SN [83]. This finding reinforces the hypothesis that aging is associated with decreased dopaminergic control of balanced activity between the direct and indirect pathways and therefore failed to report direct evidence for an imbalance between the direct and indirect pathway. From studies on the striatal dopaminergic synapse and the responses of motor decline to dopaminergic treatment, there is an accumulation of evidence that raises questions and controversies about whether aging and PD [52] exhibit similar dysfunctions in the basal ganglia circuitry. 2.5. Striatal dopaminergic system, aging and Parkinson’s disease Experimental studies in primates showed that even in the absence of an overall neuronal loss, changes in the characteristics of dopaminergic cells reflect functional deficits and increased vulnerability to injury with age [23]. In addition, the overall agerelated decrease in striatal dopamine neurotransmission may limit some compensatory responses to the decrement in DA cell loss in PD [94] and therefore, in line with Collier et al. [95], have the potential to decrease the threshold for the expression of parkinsonian symptoms [95,96]. However, Lewy body pathology,
430
O. Darbin / Parkinsonism and Related Disorders 18 (2012) 426e432
hallmarks of PD, is less prevalent [97] than signs for parkinsonism [1] in the elderly population. Therefore, there is neither evidence to support age-dependent neurodegenerative processes as primary causes of TPD [14], nor to associate automatically, age-related parkinsonism to early stage TPD. Nevertheless, age-related parkinsonism likely contributes to age-dependent occurrences of complications in patients with TPD [96] such as changes in clinical symptoms [98] and response to treatments [99,100]. 3. Conclusion Normal aging is associated with circuitry alterations in the basal ganglia. The effects of aging on the striatal dopaminergic synapse differ from those resulting from TPD. The specific effects of aging on dopaminergic neurotransmission in the striatum likely contribute to both age-related parkinsonism and the poor improvement in mobility with dopaminergic treatment. These differences raise questions about whether age-related parkinsonism and TPD share similar basal ganglia dysfunctions. It is expected that the identification of electrophysiological hallmarks of aging in the basal ganglia will aid in developing a functional model of the aging motor circuitry. The extent of age-related dysfunction at the level of the striatal dopaminergic synapse suggests a shift of focus toward nondopaminergic anti-parkinsonian medications [101] and more comparisons with atypical parkinsonian conditions. Ultimately, identification of treatments that alleviate age-related parkinsonism may also benefit the long-term management of aging patients with TPD. Acknowledgment Dr O. Darbin is principally supported by the Department of Neurology University of South Alabama College of Medicine, Mobile, AL and by the Division of System Neurophysiology at the National Institute of Japan for Physiological Sciences (NIJPS-Okasaki). The author would like to thank Dr D.E. Salter and Susan Calne for the editing of the manuscript. This manuscript is dedicated to the memory of Pr R. Joly. Full financial disclosure Nothing to report. References [1] Bennett DA, Beckett LA, Murray AM, Shannon KM, Goetz CG, Pilgrim DM, et al. Prevalence of parkinsonian signs and associated mortality in a community population of older people. N Engl J Med 1996;334:71e6. [2] Ingram DK. Age-related decline in physical activity: generalization to nonhumans. Med Sci Sports Exerc 2000;32:1623e9. [3] Wilson RS, Schneider JA, Beckett LA, Evans DA, Bennett DA. Progression of gait disorder and rigidity and risk of death in older persons. Neurology 2002; 58:1815e9. [4] Larsson L, Ramamurthy B. Aging-related changes in skeletal muscle. Mechanisms and interventions. Drugs Aging 2000;17:303e16. [5] Dickstein DL, Kabaso D, Rocher AB, Luebke JI, Wearne SL, Hof PR. Changes in the structural complexity of the aged brain. Aging Cell 2007;6:275e84. [6] Middleton FA, Strick PL. Basal ganglia and cerebellar loops: motor and cognitive circuits. Brain Res Brain Res Rev 2000;31:236e50. [7] Alexander GE, Crutcher MD. Functional architecture of basal ganglia circuits: neural substrates of parallel processing. Trends Neurosci 1990;13:266e71. [8] Delong MR. Primate models of movement-disorders of basal ganglia origin. Trends Neurosci 1990;13:281e5. [9] Turner RS, Grafton ST, Votaw JR, Delong MR, Hoffman JM. Motor subcircuits mediating the control of movement velocity: a PET study. J Neurophysiol 1998;80:2162e76. [10] Obeso JA, Rodriguez MC, DeLong MR. Basal ganglia pathophysiology. A critical review. Adv Neurol 1997;74:3e18. [11] Saint-Cyr JA. Basal ganglia: functional perspectives and behavioral domains. Adv Neurol 2005;96:1e16.
[12] Cruz-Muros I, Afonso-Oramas D, Abreu P, Barroso-Chinea P, Rodriguez M, Gonzalez MC, et al. Aging of the rat mesostriatal system: differences between the nigrostriatal and the mesolimbic compartments. Exp Neurol 2007;204: 147e61. [13] Haycock JW, Becker L, Ang L, Furukawa Y, Hornykiewicz O, Kish SJ. Marked disparity between age-related changes in dopamine and other presynaptic dopaminergic markers in human striatum. J Neurochem 2003;87:574e85. [14] Kish SJ, Shannak K, Rajput A, Deck JH, Hornykiewicz O. Aging produces a specific pattern of striatal dopamine loss: implications for the etiology of idiopathic Parkinson’s disease. J Neurochem 1992;58:642e8. [15] Lloyd KG, Hornykiewicz O. Occurrence and distribution of aromatic L-amino acid (L-DOPA) decarboxylase in the human brain. J Neurochem 1972;19: 1549e59. [16] Harada N, Nishiyama S, Satoh K, Fukumoto D, Kakiuchi T, Tsukada H. Agerelated changes in the striatal dopaminergic system in the living brain: a multiparametric PET study in conscious monkeys. Synapse 2002;45:38e45. [17] Suzuki M, Hatano K, Sakiyama Y, Kawasumi Y, Kato T, Ito K. Age-related changes of dopamine D1-like and D2-like receptor binding in the F344/N rat striatum revealed by positron emission tomography and in vitro receptor autoradiography. Synapse 2001;41:285e93. [18] Wang Y, Chan GL, Holden JE, Dobko T, Mak E, Schulzer M, et al. Agedependent decline of dopamine D1 receptors in human brain: a PET study. Synapse 1998;30:56e61. [19] Giorgi O, De Montis G, Porceddu ML, Mele S, Calderini G, Toffano G, et al. Developmental and age-related changes in D1-dopamine receptors and dopamine content in the rat striatum. Brain Res 1987;432:283e90. [20] Stark AK, Pakkenberg B. Histological changes of the dopaminergic nigrostriatal system in aging. Cell Tissue Res 2004;318:81e92. [21] Ota M, Yasuno F, Ito H, Seki C, Nozaki S, Asada T, et al. Age-related decline of dopamine synthesis in the living human brain measured by positron emission tomography with L-[beta-11C]DOPA. Life Sci 2006;79:730e6. [22] Ishida Y, Okawa Y, Ito S, Shirokawa T, Isobe K. Age-dependent changes in dopaminergic projections from the substantia nigra pars compacta to the neostriatum. Neurosci Lett 2007;418:257e61. [23] McCormack AL, Di Monte DA, Delfani K, Irwin I, DeLanney LE, Langston WJ, et al. Aging of the nigrostriatal system in the squirrel monkey. J Comp Neurol 2004;471:387e95. [24] Colebrooke RE, Humby T, Lynch PJ, McGowan DP, Xia J, Emson PC. Agerelated decline in striatal dopamine content and motor performance occurs in the absence of nigral cell loss in a genetic mouse model of Parkinson’s disease. Eur J Neurosci 2006;24:2622e30. [25] Fearnley JM, Lees AJ. Ageing and Parkinson’s disease: substantia nigra regional selectivity. Brain 1991;114(Pt 5):2283e301. [26] Emborg ME, Ma SY, Mufson EJ, Levey AI, Taylor MD, Brown WD, et al. Agerelated declines in nigral neuronal function correlate with motor impairments in rhesus monkeys. J Comp Neurol 1998;401:253e65. [27] Barili P, De Carolis G, Zaccheo D, Amenta F. Sensitivity to ageing of the limbic dopaminergic system: a review. Mech Ageing Dev 1998;106:57e92. [28] Reeves S, Bench C, Howard R. Ageing and the nigrostriatal dopaminergic system. Int J Geriatr Psychiatry 2002;17:359e70. [29] Smith CD, Chebrolu H, Wekstein DR, Schmitt FA, Markesbery WR. Age and gender effects on human brain anatomy: a voxel-based morphometric study in healthy elderly. Neurobiol Aging 2007;28:1075e87. [30] Gunning-Dixon FM, Head D, McQuain J, Acker JD, Raz N. Differential aging of the human striatum: a prospective MR imaging study. AJNR Am J Neuroradiol 1998;19:1501e7. [31] Good CD, Johnsrude IS, Ashburner J, Henson RN, Friston KJ, Frackowiak RS. A voxel-based morphometric study of ageing in 465 normal adult human brains. Neuroimage 2001;14:21e36. [32] Raz N, Gunning-Dixon FM, Head D, Dupuis JH, Acker JD. Neuroanatomical correlates of cognitive aging: evidence from structural magnetic resonance imaging. Neuropsychology 1998;12:95e114. [33] Pakkenberg H, Andersen BB, Burns RS, Pakkenberg B. A stereological study of substantia nigra in young and old rhesus monkeys. Brain Res 1995;693:201e6. [34] Kubis N, Faucheux BA, Ransmayr G, Damier P, Duyckaerts C, Henin D, et al. Preservation of midbrain catecholaminergic neurons in very old human subjects. Brain 2000;123:366e73. [35] McNeill TH, Koek LL. Differential effects of advancing age on neurotransmitter cell loss in the substantia nigra and striatum of C57BL/6N mice. Brain Res 1990;521:107e17. [36] Emerich DF, McDermott P, Krueger P, Banks M, Zhao J, Marszalkowski J, et al. Locomotion of aged rats: relationship to neurochemical but not morphological changes in nigrostriatal dopaminergic neurons. Brain Res Bull 1993; 32:477e86. [37] Irwin I, DeLanney LE, McNeill T, Chan P, Forno LS, Murphy Jr GM, et al. Aging and the nigrostriatal dopamine system: a non-human primate study. Neurodegeneration 1994;3:251e65. [38] Salvatore MF, Apparsundaram S, Gerhardt GA. Decreased plasma membrane expression of striatal dopamine transporter in aging. Neurobiol Aging 2003; 24:1147e54. [39] McGeer PL, McGeer EG, Suzuki JS. Aging and extrapyramidal function. Arch Neurol 1977;34:33e5. [40] Mann DM, Yates PO. The effects of ageing on the pigmented nerve cells of the human locus caeruleous and substantia nigra. Acta Neuropathol 1979;47:93e7.
O. Darbin / Parkinsonism and Related Disorders 18 (2012) 426e432 [41] Thiessen B, Rajput AH, Laverty W, Desai H. Age, environments, and the number of substantia nigra neurons. Adv Neurol 1990;53:201e6. [42] Ma SY, Roytt M, Collan Y, Rinne JO. Unbiased morphometrical measurements show loss of pigmented nigral neurones with ageing. Neuropathol Appl Neurobiol 1999;25:394e9. [43] Siddiqi Z, Kemper TL, Killiany R. Age-related neuronal loss from the substantia nigra-pars compacta and ventral tegmental area of the rhesus monkey. J Neuropathol Exp Neurol 1999;58:959e71. [44] Cabello CR, Thune JJ, Pakkenberg H, Pakkenberg B. Ageing of substantia nigra in humans: cell loss may be compensated by hypertrophy. Neuropathol Appl Neurobiol 2002;28:283e91. [45] Chu Y, Kompoliti K, Cochran EJ, Mufson EJ, Kordower JH. Age-related decreases in Nurr1 immunoreactivity in the human substantia nigra. J Comp Neurol 2002;450:203e14. [46] Vaillancourt DE, Spraker MB, Prodoehl J, Zhou XJ, Little DM. Effects of aging on the ventral and dorsal substantia nigra using diffusion tensor imaging. Neurobiol Aging; 2010. [47] Bernheimer H, Birkmayer W, Hornykiewicz O, Jellinger K, Seitelberger F. Brain dopamine and the syndromes of Parkinson and Huntington. J Neurol Sci 1973;20:415e55. [48] Miguez JM, Aldegunde M, Paz-Valinas L, Recio J, Sanchez-Barcelo E. Selective changes in the contents of noradrenaline, dopamine and serotonin in rat brain areas during aging. J Neural Transm 1999;106:1089e98. [49] Udenfriend S. Tyrosine hydroxylase. Pharmacol Rev 1966;18:43e51. [50] Yurek DM, Hipkens SB, Hebert MA, Gash DM, Gerhardt GA. Age-related decline in striatal dopamine release and motoric function in brown Norway/ Fischer 344 hybrid rats. Brain Res 1998;791:246e56. [51] Gerhardt GA, Cass WA, Yi A, Zhang Z, Gash DM. Changes in somatodendritic but not terminal dopamine regulation in aged rhesus monkeys. J Neurochem 2002;80:168e77. [52] Hurley PJ, Elsworth JD, Whittaker MC, Roth RH, Redmond Jr DE. Aged monkeys as a partial model for Parkinson’s disease. Pharmacol Biochem Behav 2011;99:324e32. [53] Gozlan H, Daval G, Verge D, Spampinato U, Fattaccini CM, Gallissot MC, et al. Aging associated changes in serotoninergic and dopaminergic pre- and postsynaptic neurochemical markers in the rat brain. Neurobiol Aging 1990; 11:437e49. [54] Dluzen DE, McDermott JL, Ramirez VD. Changes in dopamine release in vitro from the corpus striatum of young versus aged rats as a function of infusion modes of L-dopa, potassium, and amphetamine. Exp Neurol 1991;112: 153e60. [55] Joseph JA, Dalton TK, Hunt WA. Age-related decrements in the muscarinic enhancement of Kþ-evoked release of endogenous striatal dopamine: an indicator of altered cholinergic-dopaminergic reciprocal inhibitory control in senescence. Brain Res 1988;454:140e8. [56] Nakano M, Mizuno T. Age-related changes in the metabolism of neurotransmitters in rat striatum: a microdialysis study. Mech Ageing Dev 1996; 86:95e104. [57] Rose GM, Gerhardt GA, Conboy GL, Hoffer BJ. Age-related alterations in monoamine release from rat striatum: an in vivo electrochemical study. Neurobiol Aging 1986;7:77e82. [58] Santiago M, Machado A, Cano J. Effects of age and dopamine agonists and antagonists on striatal dopamine release in the rat: an in vivo microdialysis study. Mech Ageing Dev 1993;67:261e7. [59] Gerhardt GA, Cass WA, Henson M, Zhang Z, Ovadia A, Hoffer BJ, et al. Agerelated changes in potassium-evoked overflow of dopamine in the striatum of the Rhesus monkey. Neurobiol Aging 1995;16:939e46. [60] Levitt M, Spector S, Sjoerdsma A, Udenfriend S. Elucidation of the ratelimiting step in norepinephrine biosynthesis in the perfused guinea-pig heart. J Pharmacol Exp Ther 1965;148:1e8. [61] Martin WRW, Palmer MR, Patlak CS, Calne DB. Nigrostriatal function in humans studied with positron emission tomography. Ann Neurol 1989;26: 535e42. [62] Cordes M, Snow BJ, Cooper S, Schulzer M, Pate BD, Ruth TJ, et al. Agedependent decline of nigrostriatal dopaminergic function: a positron emission tomographic study of grandparents and their grandchildren. Ann Neurol 1994;36:667e70. [63] Sossi V, de la Fuente-Fernandez R, Schulzer M, Troiano AR, Ruth TJ, Stoessl AJ. Dopamine transporter relation to dopamine turnover in Parkinson’s disease: a positron emission tomography study. Ann Neurol 2007;62:468e74. [64] Biju G, de la Fuente-Fernandez R. Dopaminergic function and progression of Parkinson’s disease: PET findings. Parkinsonism Relat Disord 2009;15(Suppl. 4):S38e40. [65] Hebert MA, Larson GA, Zahniser NR, Gerhardt GA. Age-related reductions in [3H]WIN 35,428 binding to the dopamine transporter in nigrostriatal and mesolimbic brain regions of the fischer 344 rat. J Pharmacol Exp Ther 1999; 288:1334e9. [66] Shimizu I, Prasad C. Relationship between [3H]mazindol binding to dopamine uptake sites and [3H]dopamine uptake in rat striatum during aging. J Neurochem 1991;56:575e9. [67] Erixon-Lindroth N, Farde L, Wahlin TB, Sovago J, Halldin C, Backman L. The role of the striatal dopamine transporter in cognitive aging. Psychiatry Res 2005;138:1e12. [68] van Dyck CH, Seibyl JP, Malison RT, Laruelle M, Zoghbi SS, Baldwin RM, et al. Age-related decline in dopamine transporters: analysis of striatal subregions,
[69]
[70]
[71]
[72]
[73]
[74]
[75]
[76]
[77]
[78]
[79]
[80] [81]
[82] [83]
[84]
[85] [86] [87] [88]
[89]
[90] [91]
[92]
[93]
[94]
[95]
431
nonlinear effects, and hemispheric asymmetries. Am J Geriatr Psychiatry 2002;10:36e43. Cruz-Muros I, Afonso-Oramas D, Abreu P, Perez-Delgado MM, Rodriguez M, Gonzalez-Hernandez T. Aging effects on the dopamine transporter expression and compensatory mechanisms. Neurobiol Aging; 2007. Mozley LH, Gur RC, Mozley PD, Gur RE. Striatal dopamine transporters and cognitive functioning in healthy men and women. Am J Psychiatry 2001;158: 1492e9. Friedemann MN, Gerhardt GA. Regional effects of aging on dopaminergic function in the Fischer-344 rat. Neurobiol Aging 1992;13: 325e32. Hebert MA, Gerhardt GA. Age-related changes in the capacity, rate, and modulation of dopamine uptake within the striatum and nucleus accumbens of Fischer 344 rats: an in vivo electrochemical study. J Pharmacol Exp Ther 1999;288:879e87. Elsworth JD, Brittan MS, Taylor JR, Sladek Jr JR, Redmond Jr DE, Innis RB, et al. Upregulation of striatal D2 receptors in the MPTP-treated vervet monkey is reversed by grafts of fetal ventral mesencephalon: an autoradiographic study. Brain Res 1998;795:55e62. Morissette M, Goulet M, Calon F, Falardeau P, Blanchet PJ, Bedard PJ, et al. Changes of D1 and D2 dopamine receptor mRNA in the brains of monkeys lesioned with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine: correction with chronic administration of L-3,4-dihydroxyphenylalanine. Mol Pharmacol 1996;50:1073e9. Rinne JO, Laihinen A, Ruottinen H, Ruotsalainen U, Nagren K, Lehikoinen P, et al. Increased density of dopamine D2 receptors in the putamen, but not in the caudate nucleus in early Parkinson’s disease: a PET study with [11C] raclopride. J Neurol Sci 1995;132:156e61. Gagnon C, Gomez-Mancilla B, Markstein R, Bedard PJ, Di Paolo T. Effect of adding the D-1 agonist CY 208-243 to chronic bromocriptine treatment of MPTP-monkeys: regional changes of brain dopamine receptors. Prog Neuropsychopharmacol Biol Psychiatry 1995;19:667e76. Yokochi M. Reevaluation of levodopa therapy for the treatment of advanced Parkinson’s disease. Parkinsonism Relat Disord 2009;15(Suppl. 1):S25e30. Newman RP, LeWitt PA, Jaffe M, Calne DB, Larsen TA. Motor function in the normal aging population: treatment with levodopa. Neurology 1985;35: 571e3. Willemssen R, Falkenstein M, Schwarz M, Muller T, Beste C. Effects of aging, Parkinson’s disease, and dopaminergic medication on response selection and control. Neurobiol Aging 2011;32:327e35. White NJ, Barnes TR. Senile parkinsonism, a study of current treatment. Age Ageing 1981;10:81e6. Diederich NJ, Moore CG, Leurgans SE, Chmura TA, Goetz CG. Parkinson disease with old-age onset: a comparative study with subjects with middleage onset. Arch Neurol 2003;60:529e33. Frank C, Pari G, Rossiter JP. Approach to diagnosis of Parkinson disease. Can Fam Physician 2006;52:862e8. Zhang Z, Andersen A, Grondin R, Barber T, Avison R, Gerhardt G, et al. Pharmacological MRI mapping of age-associated changes in basal ganglia circuitry of awake Rhesus monkeys. NeuroImage 2001;14:1159e67. Ingram DK, Ikari H, Umegaki H, Chernak JM, Roth GS. Application of gene therapy to treat age-related loss of dopamine D2 receptor. Exp Gerontol 1998;33:793e804. Gerfen CR, Surmeier DJ. Modulation of striatal projection systems by dopamine. Annu Rev Neurosci; 2010. Galvan A, Wichmann T. Pathophysiology of parkinsonism. Clin Neurophysiol 2008;119:1459e74. Nambu A. A new dynamic model of the cortico-basal ganglia loop. Prog Brain Res 2004;143:461e6. Obeso JA, Marin C, Rodriguez-Oroz C, Blesa J, Benitez-Temino B, MenaSegovia J, et al. The basal ganglia in Parkinson’s disease: current concepts and unexplained observations. Ann Neurol 2008;64(Suppl. 2):S30e46. Tang JK, Moro E, Mahant N, Hutchison WD, Lang AE, Lozano AM, et al. Neuronal firing rates and patterns in the globus pallidus internus of patients with cervical dystonia differ from those with Parkinson’s disease. J Neurophysiol 2007;98:720e9. Ward NS, Frackowiak RS. Age-related changes in the neural correlates of motor performance. Brain 2003;126:873e88. Mattay VS, Fera F, Tessitore A, Hariri AR, Das S, Callicott JH, et al. Neurophysiological correlates of age-related changes in human motor function. Neurology 2002;58:630e5. Calautti C, Serrati C, Baron JC. Effects of age on brain activation during auditory-cued thumb-to-index opposition: a positron emission tomography study. Stroke 2001;32:139e46. Wu T, Zang Y, Wang L, Long X, Li K, Chan P. Normal aging decreases regional homogeneity of the motor areas in the resting state. Neurosci Lett 2007;423: 189e93. Ohashi S, Mori A, Kurihara N, Mitsumoto Y, Nakai M. Age-related severity of dopaminergic neurodegeneration to MPTP neurotoxicity causes motor dysfunction in C57BL/6 mice. Neurosci Lett 2006;401:183e7. Collier TJ, Lipton J, Daley BF, Palfi S, Chu Y, Sortwell C, et al. Aging-related changes in the nigrostriatal dopamine system and the response to MPTP in nonhuman primates: diminished compensatory mechanisms as a prelude to parkinsonism. Neurobiol Dis 2007;26:56e65.
432
O. Darbin / Parkinsonism and Related Disorders 18 (2012) 426e432
[96] Adler CH, Hentz JG, Joyce JN, Beach T, Caviness JN. Motor impairment in normal aging, clinically possible Parkinson’s disease, and clinically probable Parkinson’s disease: longitudinal evaluation of a cohort of prospective brain donors. Parkinsonism Relat Disord 2002;9:103e10. [97] Markesbery WR, Jicha GA, Liu H, Schmitt FA. Lewy body pathology in normal elderly subjects. J Neuropathol Exp Neurol 2009;68:816e22. [98] Kostic V, Przedborski S, Flaster E, Sternic N. Early development of levodopainduced dyskinesias and response fluctuations in young-onset Parkinson’s disease. Neurology 1991;41:202e5.
[99] Sossi V, de la Fuente-Fernandez R, Schulzer M, Adams J, Stoessl AJ. Agerelated differences in levodopa dynamics in Parkinson’s: implications for motor complications. Brain 2006;129:1050e8. [100] Nagayama H, Ueda M, Kumagai T, Tsukamoto K, Nishiyama Y, Nishimura S, et al. Influence of ageing on the pharmacokinetics of levodopa in elderly patients with Parkinson’s disease. Parkinsonism Relat Disord 2011;17:150e2. [101] Emborg ME, Moirano J, Raschke J, Bondarenko V, Zufferey R, Peng S, et al. Response of aged parkinsonian monkeys to in vivo gene transfer of GDNF. Neurobiol Dis 2009;36:303e11.