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Parkinsonism and Related Disorders 18 (2012) 426e432

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Parkinsonism and Related Disorders

journal homepage: www.elsevier .com/locate/parkreldis

Review

The aging striatal dopamine function

Olivier Darbin a,b,*

aDepartment of Neurology, University South Alabama, 307 University Blvd., Mobile, AL 36688, USAbDivision of System Neurophysiology, National Institute for Physiological Sciences, Okazaki, Japan

a r t i c l e i n f o

Article history:Received 27 August 2011Received in revised form23 November 2011Accepted 27 November 2011

Keywords:ElderlyCatecholamineNigro-striatal pathwayMotor activityDopamine depletion

* Corresponding author. Department of Neurology,College of Medicine, 3401 Medical Park Dr., Bldg 3,USA. Tel.: þ1 770 329 8773; fax: þ1 251 660 5924.

E-mail address: odarbin@usouthal.edu.

1353-8020/$ e see front matter � 2011 Elsevier Ltd.doi:10.1016/j.parkreldis.2011.11.025

a b s t r a c t

Movement disorders are prevalent in the elderly and may have both central and peripheral origins. Age-related parkinsonism often results in movement disorders identical to some of the cardinal symptoms oftypical Parkinson’s disease (TPD). Nevertheless, there may be limited similarity in the underlyingdysfunction of the sensory-motor circuitry since these two conditions exhibit different changes in thenigro-striatal pathway. In this short review, we highlight some of the key distinctions between aging andTPD regarding striatal dopaminergic activity and discuss them in the context of therapeutic strategies toalleviate motor decline in the elderly.

� 2011 Elsevier Ltd. All rights reserved.

Contents

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4262. Aging and striatal dopaminergic neurotransmission . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .427

2.1. Striatal dopamine metabolism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4272.2. Striatal dopamine receptors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4272.3. Age-related response to dopaminergic treatments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4272.4. Aged-related striatal dopamine alterations: what are the possible consequences on basal ganglia circuitry activity? . . . . . . . . . . . . . . . . . . . . . 4282.5. Striatal dopaminergic system, aging and Parkinson’s disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 429

3. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 430Acknowledgment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 430Full financial disclosure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 430References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 430

1. Introduction

Motor signs of parkinsonism increase with aging and affectmore than 50% of people over the age of 85 years [1]. They arepredictive of lifespan [1e3], contribute to the perception of dete-rioration in quality of life [4] and have an economical impact. In theelderly, motor symptoms with the highest prevalence include:bradykinesia (37%), gait disturbance (51%) and rigidity (43%) but

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resting tremor, a cardinal symptom of typical Parkinson’s disease(TPD), has a low prevalence (5%) in the elderly [1]. In contrast toTPD, dopaminergic replacement strategies are ineffective atrelieving the burden associated with age-related parkinsonism.Though this lack of benefit may indicate complex and diffusealterations along the motor efferent pathway [5], it may also be dueto the fact that TPD and age-related parkinsonism exhibit differentneuropathological hallmarks in the central motor circuitry.Understanding the specificities of age-related parkinsonism, incomparison toTPD, is an important step for efficient cross disciplineresearch between these two conditions. Ultimately, the identifica-tion of reversible central dysfunctions in the aging central motorcircuitry could facilitate our ability to develop new therapeutic

O. Darbin / Parkinsonism and Related Disorders 18 (2012) 426e432 427

strategies to reduce the severity of or delay the onset of parkin-sonism related to aging.

Numerous structural studies have pointed to age-relatedchanges in the basal ganglia. The basal ganglia, as part of thecortico-cortical loops within the sensory-motor circuitry, areinvolved in the planning, initiation and control of voluntarymovement [6e9]. Specifically, dopamine depletion in the majorinput nucleus of the basal ganglia, e.g. the striatum, is manifestedby the inability to initiate and cease movement, the inability tosuppress involuntary movement, an abnormality in the velocityand amount of movement, and abnormal muscle tone [9e11]. Intypical PD, the depletion in striatal dopamine is considered to bea contributing factor to akinesia which is responsive to dopaminereplacement therapy. Markers for striatal dopaminergic activities,such as enzymes [12e15] and receptors [16e19], have consistentlybeen reported as being altered [12,20e24] in the aging basalganglia. However, Lewy body pathologies and loss of dopaminergiccells in the nigro-striatal pathway, which are hallmarks for TPD (i.e.see Ref. [25]), are not reliable markers for aging [20,23,24]. Age-related parkinsonism-like symptoms have been identified inexperimental animal models [2,26]. Here, we review evidence thatage-related alterations in striatal dopamine function are differentfrom those observed in TPD and could contribute, at least partially,to the poor response of age-related parkinsonism to dopaminereplacement therapies.

2. Aging and striatal dopaminergic neurotransmission

2.1. Striatal dopamine metabolism

Aging results in morphological and neurochemical changes inthe basal ganglia that may contribute to the decline in motor,cognitive and affective functions [27e32]. Parkinsonism related toaging may occur without major decrease in the number of nigraldopaminergic cells [23,33e38], and with only moderate degener-ation of the nigro-striatal pathway (15e45%) [23,25,26,39e46].This is an important distinction from TPD for which cardinal motorsymptoms occur when nigral dopaminergic cell loss exceeds 80%[47]. When it occurs in the aging brain, dopaminergic cell loss doesnot correlate in time with the development of motor symptoms. Infact, dopamine cell loss has been shown to be more prevalent inyoung and adult subjects than middle-aged and old subjects [23].

However, aging results in decreased striatal dopaminergicactivity in rodents [24,48e50], monkeys [51], primates [52] andhumans [13,14]. Early studies showed decreased levels in dopaminetissue content in the rat striatum [53]. In aged rodents [54e58] andaged non-human primates [59], in-vivo monitoring of the extra-cellular content of dopamine (and its first metabolite) by micro-dialysis confirmed decreased base line levels and evoked responseto a high potassium challenge. From this, one can infer that dopa-mine depletion, but not dopaminergic cell loss, is a hallmark foraging 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 dopaminedepletion. Clinical studies using positron emission tomographywith 11C-labeled L-DOPA have established an age-related decreasein striatal L-DOPA utilization and dopamine synthesis in the stria-tum of the neurologically normal elderly [21]. This was alsoconfirmed in aged non-human primates that exhibit a reducedincrease in striatal dopamine levels following local administrationof a DAT inhibitor [16]. In adult mammals, the dopamine synthesisis limited by the activity of tyrosine hydroxylase (TH) [49,60] and L-DOPA decarboxylase (DDC, or AADC for aromatic amino aciddecarboxylase). In aged subjects, the activity for both TH [12e15]

and DDC [16,61,62] is decreased but their relative contribution tothe depletion in striatal dopamine remains a matter of debate[12,13] (Fig. 2). In comparison to aging, typical PD is associated withan increased striatal dopaminergic metabolism in the survivingdopaminergic terminals as the loss of DA neurons progresses in thesubstantia nigra compacta [63,64] (Fig. 2).

Aging affects not only the striatal synthesis of dopamine butalso the local activity and expression of the dopamine transporter(DAT) [65e72]. At least two mechanisms appear to be involved inage-related decline in striatal DAT function. The first mechanisminvolves a DAT redistribution away from the plasma membrane[65] consecutive to a deficit in glycosylation [38]. The secondmechanism involves a decrease in DAT binding and DAT-mRNAwhich may be a down regulation in response to the decrease inDA levels [69].

As a consequence of this, it is remarkable that both aging andTPD result in striatal dopamine depletion. However, the origins ofthe structural and metabolic alterations of this depletion in dopa-mine differ greatly between these two conditions.

2.2. Striatal dopamine receptors

The age-related decrease in striatal dopamine metabolism isalso associated with changes in local dopamine receptors. Inrodents, monkeys and humans, studies have reported an age-related decline in the binding of selective agents to either D2-[16,17] or D1-dopamine receptors [16e19]. Therefore, the expres-sion for two DA receptor families is reduced in the aged striatum(Fig. 2). This is in contrast to TPD which, in fact, exhibits anincreased expression in striatal dopamine D2 receptors (but not D1)[73e76].

Age-related alteration in the striatal dopaminergic terminalsincludes functional impairments at both pre- and post-synapticlevels. In the next paragraph, we discuss the impact of thesealterations on the effects of dopaminergic treatment for age-relatedmotor decline.

2.3. Age-related response to dopaminergic treatments

In patients with typical PD and in the first half decade oftreatment, brain dopamine replacement is beneficial for somespecific motor symptoms including bradykinesia and hypokinesia[77]. In contrast to TPD, clinical studies performed in healthyelderly humans have reported poor or no benefit from dopaminereplacement therapy (L-DOPA) on age-related motor decline. Ina double-blind crossover study in normal elderly humans, theeffects of carbidopa/levodopa have been investigated onmovementvelocity, reaction time, tremor and visual evoked responses (VER).This treatment was found to have no benefit on both motor func-tions and VER [78]. More recently, the lack of efficacy of anti-parkinsonian dopaminergic medication was also reported onevent-related potentials (ERPs) during a stimulus-response (S-R)compatibility task in elderly humans [79]. It is probable thatdecreased DDC activity in the aged striatum [12] may contribute toa poor neuronal utilization of L-DOPA and the limited benefit of thistreatment for age-related motor decline [80e82]. In addition toa weak bio-transformation of L-DOPA, DA may also have a limitedaction since aging is associated with a decreased expression instriatal post-synaptic DA receptors. In aged rhesus monkeys,systemic administration of apomorphine weakly increases motoractivities in comparatively to its effect in young primates [83].Interestingly, experimental studies in rodents have shown that age-related decline in motor function is not reversed by D2R genetransfer in the striatum [84], suggesting that other mechanisms,downstream to post-synaptic dopaminergic receptors, may also

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: InTPD 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 mostlyexplained by a substantial decrease in dopamine synthesize in the nigro-striatal terminals.

O. Darbin / Parkinsonism and Related Disorders 18 (2012) 426e432428

contribute to limit the reversal of age-related motor decline bydopaminergic treatments.

2.4. Aged-related striatal dopamine alterations: what are thepossible consequences on basal ganglia circuitry activity?

Though age-related alterations in striatal dopaminergic activityare expected to result in dysfunction in the basal ganglia, thenatures of these changes remain sparsely documented.

The current functional model of basal ganglia for movementdisorders is founded upon two main assumptions. The first

assumption is that the direct pathway (Str-GPi/SNr) is up regulatedby the D1 receptor and the indirect pathway (Str-GPe-GPi/SNr) isdown regulated by the D2 receptor. The second assumption is thatan imbalance of activity in favor of the direct pathway enhancesmotor selection (i.e. hyperkinesia) and imbalanced activity in favorof the indirect pathway enhances motor inhibition (i.e. hypo-kinesia) [85]. In PD, the model predicts that depletion in striataldopamine can cause a down regulation of the direct pathway andup regulation of the indirect pathway. The resulting imbalance infavor of the indirect pathway is predicted to increase activity in theoutput nuclei of the basal ganglia (GPi) and, therefore, motor

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 bythe Tyrosine Hydroxylase (TH) which is transformed in Dopamine (DA) by the L-DOPA decarboxylase (DDC). Intracellular dopamine ([DA]i) is released by transporter-dependent orexocytotic 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 thedirect 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 resultingin striatal dopamine depletion. In addition, and at the post-synaptic levels, the expressions of both D1 and D2 family receptors are reduced.

O. Darbin / Parkinsonism and Related Disorders 18 (2012) 426e432 429

inhibition [86e89]. Though this model is rigorously debated, it maybe used as a reference for discussing basal ganglia dysfunction inregard to movement disorders.

In the aging striatum, depletion in both dopamine and dopa-minergic receptors has the potential to decrease the D2-mediatedinhibition on the indirect pathway and the D1-mediated excita-tion on the direct pathway. Concerning the model previously cited,it is conceivable that an increased activity in the GPi couldcontribute to age-related motor decline. A few fMRI studies haveattempted to determine age-related changes in basal gangliaactivity with a special focus on the output nuclei [90e92]. PreviousfMRI studies in the elderly have reported an aging-relatedincreased activity in the GP [93]. Due to technical limitations, theGPe and GPi were not distinguished in this last study and therefore,the study failed to identify the effects of aging specifically on theoutput nuclei of the basal ganglia (namely the GPi and the SN). Inanother study, the effects of the D1/D2 agonist apomorphine werespecifically investigated on the output nuclei of the basal ganglia[83]. In young non-human primates, systemic administration ofapomorphine increases the local measurement of blood oxygenlevel-dependency (BOLD response) in the GPi and SN [83],a response consistent with a decreased activity in the output nucleiand hyperkinesias, as predicted by the model. In aged primates, the

same pharmacological challenge failed to affect the activities in GPiand SN [83]. This finding reinforces the hypothesis that aging isassociated with decreased dopaminergic control of balancedactivity between the direct and indirect pathways and thereforefailed to report direct evidence for an imbalance between the directand indirect pathway.

From studies on the striatal dopaminergic synapse and theresponses of motor decline to dopaminergic treatment, there is anaccumulation of evidence that raises questions and controversiesabout whether aging and PD [52] exhibit similar dysfunctions in thebasal ganglia circuitry.

2.5. Striatal dopaminergic system, aging and Parkinson’s disease

Experimental studies in primates showed that even in theabsence of an overall neuronal loss, changes in the characteristics ofdopaminergic cells reflect functional deficits and increasedvulnerability to injury with age [23]. In addition, the overall age-related decrease in striatal dopamine neurotransmission maylimit some compensatory responses to the decrement in DA cellloss in PD [94] and therefore, in line with Collier et al. [95], have thepotential to decrease the threshold for the expression of parkin-sonian symptoms [95,96]. However, Lewy body pathology,

O. Darbin / Parkinsonism and Related Disorders 18 (2012) 426e432430

hallmarks of PD, is less prevalent [97] than signs for parkinsonism[1] in the elderly population. Therefore, there is neither evidence tosupport age-dependent neurodegenerative processes as primarycauses of TPD [14], nor to associate automatically, age-relatedparkinsonism to early stage TPD. Nevertheless, age-relatedparkinsonism likely contributes to age-dependent occurrences ofcomplications in patients with TPD [96] such as changes in clinicalsymptoms [98] and response to treatments [99,100].

3. Conclusion

Normal aging is associated with circuitry alterations in the basalganglia. The effects of aging on the striatal dopaminergic synapsediffer from those resulting from TPD. The specific effects of aging ondopaminergic neurotransmission in the striatum likely contribute toboth age-related parkinsonism and the poor improvement inmobility with dopaminergic treatment. These differences raisequestions about whether age-related parkinsonism and TPD sharesimilar basal ganglia dysfunctions. It is expected that the identifica-tion of electrophysiological hallmarks of aging in the basal gangliawill aid in developing a functionalmodel of the agingmotor circuitry.

The extent of age-related dysfunction at the level of the striataldopaminergic synapse suggests a shift of focus toward non-dopaminergic anti-parkinsonian medications [101] and morecomparisons with atypical parkinsonian conditions. Ultimately,identification of treatments that alleviate age-related parkinsonismmay also benefit the long-termmanagement of aging patients withTPD.

Acknowledgment

Dr O. Darbin is principally supported by the Department ofNeurology University of South Alabama College of Medicine,Mobile, AL and by the Division of System Neurophysiology at theNational Institute of Japan for Physiological Sciences (NIJPS-Oka-saki). The author would like to thank Dr D.E. Salter and Susan Calnefor the editing of the manuscript. This manuscript is dedicated tothe memory of Pr R. Joly.

Full financial disclosure

Nothing to report.

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