- Email: [email protected]
Minor retinal degeneration in Parkinson’s disease
Medical Hypotheses 76 (2011) 194–196
Contents lists available at ScienceDirect
Medical Hypotheses journal homepage: www.elsevier.com/locate/mehy
Minor retinal degeneration in Parkinson’s disease Yan Ming Huang, Zheng Qin Yin ⇑ Southwest Hospital, Southwest Eye Hospital, Third Military Medical University, Chongqing 400038, People’s Republic of China
a r t i c l e
i n f o
Article history: Received 6 April 2010 Accepted 8 September 2010
s u m m a r y Parkinson’s disease is a neurodegenerative disorder with selective and progressive loss of dopaminergic neurons in substantia nigra. Studies on Parkinson’s disease patients and dopamine-depleted animals indicate that dopaminergic neurons in the retina degenerate due to the genetic and environmental factors that cause dopaminergic neuron loss in the substantia nigra. Besides motor and non-motor symptoms, visual symptoms are common in Parkinson’s disease patients, ranging from complaints of reading and driving difficulties, to complex visual hallucinations. The delicate network of various neurons in the retina ensures the accuracy of visual signal transmission, and dopamine is primarily a modulator in this complicated process. In retinitis pigmentosa, the gradual loss of photoreceptors causes gross remodeling of the neural retina and eventually loss of visual capacity. We hypothesize that the retina in Parkinson’s disease patients undergoes comparatively minor degeneration due to progressive loss of dopaminergic neurons, which are less in amount and auxiliary in function compared to photoreceptors, and thus lead to various visual dysfunctions. Ó 2010 Elsevier Ltd. All rights reserved.
Introduction
Our hypothesis
Parkinson’s disease (PD) is a neurodegenerative disorder with an estimated incidence of 1% in people over 60 years of age [1,2]. The progressive loss of dopaminergic neurons in substantia nigra in PD is due to a complex interaction among multiple predisposing genes and environmental contributions [3]. Since its first description by James Parkinson as ‘the shaking palsy’, more and more studies have revealed it to be a multi-system disorder with a wide variety of motor and non-motor symptoms. In addition, visual defects have also been detected in PD patients [4]. Visual signals in the retina transmit in two directions—vertically and horizontally. Vertical neurotransmission takes place predominantly from photoreceptor to bipolar cell to ganglion cell. Horizontal neurotransmission takes place in both the outer and inner plexiform layers, modulating the signal flow through the vertical pathway [5]. The dopaminergic neuron is one of the various modulators in the inner plexiform layer. The gradual loss of photoreceptors in retinitis pigmentosa (RP) often results in deafferentation of the neural retina, and the neural retina responds to this challenge by remodeling, first by subtle changes in neuronal structure and later by large-scale reorganization, and eventually loss of visual capacity [6]. However, whether the progressive loss of dopamine (DA) neurons in the retina of PD patients would trigger structural deformation and affect the function of the retina as in RP remains to be elucidated.
As dopaminergic neurons distribute evenly throughout the retina at a low density of 10–60 cells/mm2 [7], and primarily play a modulating role in visual transmission, we hypothesize that the progressive loss of dopaminergic neurons won’t elicit such major remodeling of the neural retina due to deafferentation as RP, but it will surely have minor effects on retinal structure and change the visual signal flow through the retina, and thus lead to various visual dysfunctions in PD patients.
⇑ Corresponding author. Tel.: +86 23 68754401; fax: +86 23 65460711. E-mail address: [email protected] (Z.Q. Yin). 0306-9877/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved. doi:10.1016/j.mehy.2010.09.016
DA modulation in the retina Tyrosine hydroxylase (TH) is the rate-limiting enzyme in the synthesis of DA and hence identifies dopaminergic neurons in the retina. In mammalian retinas, TH immunoreactive dopaminergic neurons include one subtype of amacrine cells (AC) and interplexiform cells (IPC) [4,7]. Dopaminergic neurons respond to light by a sustained depolarization [8], which increases Ca2+ entry into the cell, and then DA is released from the cell body and processes [9]. DA activates D1 and D2 receptors distributed throughout the retina and affect almost all the neurons in the retina [10]. Multiple DA-dependent physiological processes indicate that DA suppresses the transmission of rod-driven visual information from the peripheral retina in low-light, and favors cone-mediated, high contrast vision [11]. Dopaminergic interplexiform cells, which send processes to both the inner and outer plexiform layers, form a feedback loop regulating the level of horizontal cell coupling and thus the diameter of their receptive fields which code for contrast
Y.M. Huang, Z.Q. Yin / Medical Hypotheses 76 (2011) 194–196
[4]. In addition, DA reduces the surrounding responses of the OFFcenter ganglion cells and provides spatial contrast sensitivity and color vision [12,13]. Recently, it was found that DA also has multiple trophic roles in retinal function related to circadian rhythmicity, cell survival and eye growth [14].
195
Parkinson’s disease [35]. These alternations in PD patients’ retina indicated that the axons of ganglion cell underwent severe deformation due to DA deficiency.
Correlation between structural and functional changes Structural changes in the retina of DA-depleted animals Six-hydroxydopamine (6-OHDA) and 1-methyl-4-phenyl1,2,3,6-tetrahydropyridine (MPTP) have been used extensively to induce dopaminergic neurodegeneration in various animal models. It was found that in young quails treated with 6-OHDA, the density of retinal dopaminergic neurons significantly decreased and the remaining DA cell bodies became swollen, and their fine beaded processes disappeared [15]. A reduction in retinal dopaminergic neurons was also reported in rabbits [16], and monkeys [17] treated with MPTP. Visual dysfunctions of DA-depleted animals In various animals, DA depletion by 6-OHDA or MPTP leads to a decline in both visual acuity and contrast sensitivity [15]. The visual evoked potentials (VEP) recorded in these DA-depleted animals showed reductions in amplitude and prolongation of latency [15,18]. Decreases in ERG b wave and oscillatory potentials were also characteristic in these animals [16,19]. Drugs such as levodopa (L-DOPA) were found to be able to improve visual contrast sensitivity [20] and visual acuity [21]. And further studies indicated that in these DA-depleted animals, treatment with LDOPA produced transient recovery of abnormal ERG and VEP responses [18]. These facts implied that the above visual dysfunctions in these animals could be attributed to the depletion of DA in the retina. Visual dysfunctions of PD patients Visual dysfunctions involved in PD include impaired visual acuity [22], abnormal contrast sensitivity [13,23,24], deficits in color vision [25,26], abnormal motion perception [27], and visual hallucinations [28]. Contrast sensitivity is uniformly diminished in all frequencies in PD patients [13,29], and this can be correlated with the role of DA interplexiform cells on the receptive fields of horizontal cells coding for contrasts. The decrease of ERG b wave and delay of VEP latency in PD patients are identical to that observed in the DA-depleted animals [30]. Numerous evidences indicate that these abnormalities in visual capacity can be totally or partly attributed to retinal dysfunction [31], and can be reversed with the administration of L-DOPA [32]. In the healthy retina, treatment with DA blocker or D2 antagonist, mimics the same alternation seen in the PD patients [33]. Structural changes in the retina of PD patients Structural degeneration of the retina has been reported in PD. Post-mortem studies of PD patients indicated that TH immunoreactivity of dopaminergic neurons was reduced [4] and DA concentration in the retina was closely related to patients’ dosing conditions [34]. In addition, the decrease of DA innervations in the central area is obvious in PD patients [4]. These aspects do suggest a degenerative process in the dopaminergic neurons in the retina of PD patients. Besides, it was found that the mean retinal nerve fiber layer (RNFL) thickness, macular thickness and volume were significantly reduced in PD patients. And the reduction in RNFL thickness and macular thickness was inversely correlated with the severity of
Visual dysfunctions observed in PD patients are identical to those found in DA-depleted animals, thus suggesting a degenerative process of DA system in the retina of PD patients. Studies on the structural changes of the retina in PD patients have confirmed the degenerative process of dopaminergic neurons, including reductions in DA concentration, cell number, and DA innervation. As DA plays its role as modulator through direct synaptic contacts and the so-called ‘‘volume transmission” [36], which are the downstream effects after dopaminergic neuron degeneration in the visual network? An early electron microscope study on MPTPtreated rabbits [37] demonstrated some nuclear inclusions which indicate accelerated ageing in a number of amacrine cells and ganglion cells, but not the dopaminergic amacrines. This might due to the hyperactivity of the post-synaptic neurons induced by a decrease in DA metabolism. Also the reduction in RNFL thickness in PD patients might also be attributed to atrophy of the axons of ganglion cells in case of decreased DA input. These evidences confirm our hypothesis that the retina is a site of structural and functional change in Parkinson’s disease, retinal neurons and the visual network did undergo a degeneration process. However, previous studies on the retina of PD patients mostly focused on dopaminergic neurons, changes that involve other retinal neurons and the entire visual network need to be further addressed.
Issues that need to be addressed As DA exerts effects on the majority of retinal neurons, do actual alterations in other retinal neurons and reconstruction of visual network occur in PD patients due to the degeneration of dopaminergic neurons? DA is important in modulating the efficiency of other neurotransmitters such as glutamate, GABA and glycine in the retina [38]. Visual dysfunctions that results from DA depletion may involve long-term complex synaptic effects. As all visual dysfunctions must have their structural basis, they might be used as guidelines in exploring structural changes of the retina in PD patients. For example, the diminished contrast sensitivity observed in PD patients might be due to more strongly coupled horizontal cells and/or amacrines in the ‘‘absence” of DA [39]. Then studies on the gap-junction coupling of horizontal cells and/or amacrines in DA-depleted animals are needed to support the hypothesis. Methods in studying the morphological changes of various neurons and the remodeling of visual network in retinitis pigmentosa can also be used. Clinical motor and non-motor symptoms arise when 80% of dopaminergic neurons in substantia nigra were damaged. Whether the rate of dopaminergic neuron degeneration in the retina remains the same as that in substantia nigra is currently unknown. Increasing evidences indicate that visual dysfunction progresses with motor disability in PD and fluctuates in parallel with motor fluctuations [40]. In addition, further studies need to address the effects of L-DOPA on retinal structure and visual function. Postmortem studies have already showed that L-DOPA therapy could elevate DA concentration in the retina. Also, the effectiveness of L-DOPA on reversing visual dysfunctions has also been confirmed in PD patients and DA-depleted animals. However, the question remains: will L-DOPA therapy change the degeneration process of the retina induced by gradual loss of dopaminergic neurons? The therapy certainly does not have the ability to stop the degeneration
196
Y.M. Huang, Z.Q. Yin / Medical Hypotheses 76 (2011) 194–196
process, as a significant reduction in RNFL thickness was observed in L-DOPA treated PD patients [35]. Discussion The retina is an approachable part of the brain, with comparatively simple neuron cell types and synaptic organization. If adequate evidences confirmed our hypothesis that the retina in PD patients did undergo a degeneration process after gradual loss of dopaminergic neurons, we can further infer that the same degeneration might also occur in the brain. This will help explain the complicated motor and non-motor symptoms in PD that can not be explained by DA deficiency alone. If L-DOPA therapy can not stop the retina or brain from deteriorating, is there any other method that can inhibit this degeneration process? PD indeed appears to be a complex disease in which DA deficiency plays a major role, but it’s not the only relevant factor. Conflict of interest statement None declared. Acknowledgement This work was supported by the National Basic Research Program of China, Grant No. 2007CB512203. References [1] de Rijk MC, Breteler MM, Graveland GA, et al. Prevalence of Parkinson’s disease in the elderly: the Rotterdam study. Neurology 1995;45:2143–6. [2] Trenkwalder C, Schwarz J, Gebhard J, et al. Starnberg trial on epidemiology of Parkinsonism and hypertension in the elderly. Prevalence of Parkinson’s disease and related disorders assessed by a door-to-door survey of inhabitants older than 65 years. Arch Neurol 1995;52:1017–22. [3] Nussbaum RL, Ellis CE. Alzheimer’s disease and Parkinson’s disease. N Engl J Med 2003;348:1356–64. [4] Nguyen-Legros J. Functional neuroarchitecture of the retina: hypothesis on the dysfunction of retinal dopaminergic circuitry in Parkinson’s disease. Surg Radiol Anat 1988;10:137–44. [5] Archibald NK, Clarke MP, Mosimann UP, Burn DJ. The retina in Parkinson’s disease. Brain 2009;132:1128–45. [6] Jones BW, Marc RE. Retinal remodeling during retinal degeneration. Exp Eye Res 2005;81:123–37. [7] Witkovsky P, Schutte M. The organization of dopaminergic neurons in vertebrate retinas. Vis Neurosci 1991;7:113–24. [8] Ammermuller J, Kolb H. The organization of the turtle inner retina. I. On- and off-center pathways. J Comp Neurol 1995;358:1–34. [9] Witkovsky P, Nicholson C, Rice ME, Bohmaker K, Meller E. Extracellular dopamine concentration in the retina of the clawed frog, Xenopus laevis. Proc Natl Acad Sci USA 1993;90:5667–71. [10] Nguyen-Legros J, Simon A, Caille I, Bloch B. Immunocytochemical localization of dopamine D1 receptors in the retina of mammals. Vis Neurosci 1997;14:545–51. [11] Maguire G, Hamasaki DI. The retinal dopamine network alters the adaptational properties of retinal ganglion cells in the cat. J Neurophysiol 1994;72:730–41. [12] Mills SL, Xia XB, Hoshi H, et al. Dopaminergic modulation of tracer coupling in a ganglion-amacrine cell network. Vis Neurosci 2007;24:593–608. [13] Skrandies W, Gottlob I. Alterations of visual contrast sensitivity in Parkinson’s disease. Hum Neurobiol 1986;5:255–9. [14] Witkovsky P. Dopamine and retinal function. Doc Ophthalmol 2004;108:17–40.
[15] Lee JY, Djamgoz MB. Retinal dopamine depletion in young quail mimics some of the effects of ageing on visual function. Vision Res 1997;37:1103–13. [16] Wong C, Ishibashi T, Tucker G, Hamasaki D. Responses of the pigmented rabbit retina to NMPTP, a chemical inducer of Parkinsonism. Exp Eye Res 1985;40:509–19. [17] Tatton WG, Kwan MM, Verrier MC, Seniuk NA, Theriault E. MPTP produces reversible disappearance of tyrosine hydroxylase-containing retinal amacrine cells. Brain Res 1990;527:21–31. [18] Ghilardi MF, Bodis-Wollner I, Onofrj MC, Marx MS, Glover AA. Spatial frequency-dependent abnormalities of the pattern electroretinogram and visual evoked potentials in a parkinsonian monkey model. Brain 1988;111(Pt 1):131–49. [19] Naarendorp F, Hitchock PF, Sieving PA. Dopaminergic modulation of rod pathway signals does not affect the scotopic ERG of cat at dark-adapted threshold. J Neurophysiol 1993;70:1681–91. [20] Domenici L, Trimarchi C, Piccolino M, Fiorentini A, Maffei L. Dopaminergic drugs improve human visual contrast sensitivity. Hum Neurobiol 1985;4:195–7. [21] Gottlob I, Charlier J, Reinecke RD. Visual acuities and scotomas after one week levodopa administration in human amblyopia. Invest Ophthalmol Vis Sci 1992;33:2722–8. [22] Jones RD, Donaldson IM, Timmings PL. Impairment of high-contrast visual acuity in Parkinson’s disease. Mov Disord 1992;7:232–8. [23] Delalande I, Hache JC, Forzy G, Bughin M, Benhadjali J, Destee A. Do visualevoked potentials and spatiotemporal contrast sensitivity help to distinguish idiopathic Parkinson’s disease and multiple system atrophy? Mov Disord 1998;13:446–52. [24] Langheinrich T, Tebartz van Elst L, Lagreze WA, Bach M, Lucking CH, Greenlee MW. Visual contrast response functions in Parkinson’s disease: evidence from electroretinograms, visually evoked potentials and psychophysics. Clin Neurophysiol 2000;111:66–74. [25] Silva MF, Faria P, Regateiro FS, et al. Independent patterns of damage within magno-, parvo- and koniocellular pathways in Parkinson’s disease. Brain 2005;128:2260–71. [26] Pieri V, Diederich NJ, Raman R, Goetz CG. Decreased color discrimination and contrast sensitivity in Parkinson’s disease. J Neurol Sci 2000;172:7–11. [27] Mosimann UP, Mather G, Wesnes KA, O’Brien JT, Burn DJ, McKeith IG. Visual perception in Parkinson disease dementia and dementia with Lewy bodies. Neurology 2004;63:2091–6. [28] Diederich NJ, Goetz CG, Raman R, Pappert EJ, Leurgans S, Piery V. Poor visual discrimination and visual hallucinations in Parkinson’s disease. Clin Neuropharmacol 1998;21:289–95. [29] Bodis-Wollner I. Visual deficits related to dopamine deficiency in experimental animals and Parkinson’s disease patients. Trends Neurosci 1990;13:296–302. [30] Kupersmith MJ, Shakin E, Siegel IM, Lieberman A. Visual system abnormalities in patients with Parkinson’s disease. Arch Neurol 1982;39:284–6. [31] Buttner T, Kuhn W, Patzold T, Przuntek H. L-Dopa improves colour vision in Parkinson’s disease. J Neural Transm Park Dis Dement Sect 1994;7:13–9. [32] Sartucci F, Porciatti V. Visual-evoked potentials to onset of chromatic redgreen and blue-yellow gratings in Parkinson’s disease never treated with LDopa. J Clin Neurophysiol 2006;23:431–5. [33] Stanzione P, Pierantozzi M, Semprini R, et al. Increasing doses of l-sulpiride reveal dose- and spatial frequency-dependent effects of D2 selective blockade in the human electroretinogram. Vision Res 1995;35:2659–64. [34] Harnois C, Di Paolo T. Decreased dopamine in the retinas of patients with Parkinson’s disease. Invest Ophthalmol Vis Sci 1990;31:2473–5. [35] Inzelberg R, Ramirez JA, Nisipeanu P, Ophir A. Retinal nerve fiber layer thinning in Parkinson disease. Vision Res 2004;44:2793–7. [36] Yazulla S, Studholme KM. Volume transmission of dopamine may modulate light-adaptive plasticity of horizontal cell dendrites in the recovery phase following dopamine depletion in goldfish retina. Vis Neurosci 1995;12:827–36. [37] Tucker GS, Hamasaki DI, Wong CG. Intranuclear rodlets in the rabbit retina following treatment with MPTP. Exp Eye Res 1986;42:569–83. [38] Dong CJ, Werblin FS. Dopamine modulation of GABAC receptor function in an isolated retinal neuron. J Neurophysiol 1994;71:1258–60. [39] Djamgoz MB, Hankins MW, Hirano J, Archer SN. Neurobiology of retinal dopamine in relation to degenerative states of the tissue. Vision Res 1997;37:3509–29. [40] Bodis-Wollner I. Visualizing the next steps in Parkinson disease. Arch Neurol 2002;59:1233–4.
Contents lists available at ScienceDirect
Medical Hypotheses journal homepage: www.elsevier.com/locate/mehy
Minor retinal degeneration in Parkinson’s disease Yan Ming Huang, Zheng Qin Yin ⇑ Southwest Hospital, Southwest Eye Hospital, Third Military Medical University, Chongqing 400038, People’s Republic of China
a r t i c l e
i n f o
Article history: Received 6 April 2010 Accepted 8 September 2010
s u m m a r y Parkinson’s disease is a neurodegenerative disorder with selective and progressive loss of dopaminergic neurons in substantia nigra. Studies on Parkinson’s disease patients and dopamine-depleted animals indicate that dopaminergic neurons in the retina degenerate due to the genetic and environmental factors that cause dopaminergic neuron loss in the substantia nigra. Besides motor and non-motor symptoms, visual symptoms are common in Parkinson’s disease patients, ranging from complaints of reading and driving difficulties, to complex visual hallucinations. The delicate network of various neurons in the retina ensures the accuracy of visual signal transmission, and dopamine is primarily a modulator in this complicated process. In retinitis pigmentosa, the gradual loss of photoreceptors causes gross remodeling of the neural retina and eventually loss of visual capacity. We hypothesize that the retina in Parkinson’s disease patients undergoes comparatively minor degeneration due to progressive loss of dopaminergic neurons, which are less in amount and auxiliary in function compared to photoreceptors, and thus lead to various visual dysfunctions. Ó 2010 Elsevier Ltd. All rights reserved.
Introduction
Our hypothesis
Parkinson’s disease (PD) is a neurodegenerative disorder with an estimated incidence of 1% in people over 60 years of age [1,2]. The progressive loss of dopaminergic neurons in substantia nigra in PD is due to a complex interaction among multiple predisposing genes and environmental contributions [3]. Since its first description by James Parkinson as ‘the shaking palsy’, more and more studies have revealed it to be a multi-system disorder with a wide variety of motor and non-motor symptoms. In addition, visual defects have also been detected in PD patients [4]. Visual signals in the retina transmit in two directions—vertically and horizontally. Vertical neurotransmission takes place predominantly from photoreceptor to bipolar cell to ganglion cell. Horizontal neurotransmission takes place in both the outer and inner plexiform layers, modulating the signal flow through the vertical pathway [5]. The dopaminergic neuron is one of the various modulators in the inner plexiform layer. The gradual loss of photoreceptors in retinitis pigmentosa (RP) often results in deafferentation of the neural retina, and the neural retina responds to this challenge by remodeling, first by subtle changes in neuronal structure and later by large-scale reorganization, and eventually loss of visual capacity [6]. However, whether the progressive loss of dopamine (DA) neurons in the retina of PD patients would trigger structural deformation and affect the function of the retina as in RP remains to be elucidated.
As dopaminergic neurons distribute evenly throughout the retina at a low density of 10–60 cells/mm2 [7], and primarily play a modulating role in visual transmission, we hypothesize that the progressive loss of dopaminergic neurons won’t elicit such major remodeling of the neural retina due to deafferentation as RP, but it will surely have minor effects on retinal structure and change the visual signal flow through the retina, and thus lead to various visual dysfunctions in PD patients.
⇑ Corresponding author. Tel.: +86 23 68754401; fax: +86 23 65460711. E-mail address: [email protected] (Z.Q. Yin). 0306-9877/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved. doi:10.1016/j.mehy.2010.09.016
DA modulation in the retina Tyrosine hydroxylase (TH) is the rate-limiting enzyme in the synthesis of DA and hence identifies dopaminergic neurons in the retina. In mammalian retinas, TH immunoreactive dopaminergic neurons include one subtype of amacrine cells (AC) and interplexiform cells (IPC) [4,7]. Dopaminergic neurons respond to light by a sustained depolarization [8], which increases Ca2+ entry into the cell, and then DA is released from the cell body and processes [9]. DA activates D1 and D2 receptors distributed throughout the retina and affect almost all the neurons in the retina [10]. Multiple DA-dependent physiological processes indicate that DA suppresses the transmission of rod-driven visual information from the peripheral retina in low-light, and favors cone-mediated, high contrast vision [11]. Dopaminergic interplexiform cells, which send processes to both the inner and outer plexiform layers, form a feedback loop regulating the level of horizontal cell coupling and thus the diameter of their receptive fields which code for contrast
Y.M. Huang, Z.Q. Yin / Medical Hypotheses 76 (2011) 194–196
[4]. In addition, DA reduces the surrounding responses of the OFFcenter ganglion cells and provides spatial contrast sensitivity and color vision [12,13]. Recently, it was found that DA also has multiple trophic roles in retinal function related to circadian rhythmicity, cell survival and eye growth [14].
195
Parkinson’s disease [35]. These alternations in PD patients’ retina indicated that the axons of ganglion cell underwent severe deformation due to DA deficiency.
Correlation between structural and functional changes Structural changes in the retina of DA-depleted animals Six-hydroxydopamine (6-OHDA) and 1-methyl-4-phenyl1,2,3,6-tetrahydropyridine (MPTP) have been used extensively to induce dopaminergic neurodegeneration in various animal models. It was found that in young quails treated with 6-OHDA, the density of retinal dopaminergic neurons significantly decreased and the remaining DA cell bodies became swollen, and their fine beaded processes disappeared [15]. A reduction in retinal dopaminergic neurons was also reported in rabbits [16], and monkeys [17] treated with MPTP. Visual dysfunctions of DA-depleted animals In various animals, DA depletion by 6-OHDA or MPTP leads to a decline in both visual acuity and contrast sensitivity [15]. The visual evoked potentials (VEP) recorded in these DA-depleted animals showed reductions in amplitude and prolongation of latency [15,18]. Decreases in ERG b wave and oscillatory potentials were also characteristic in these animals [16,19]. Drugs such as levodopa (L-DOPA) were found to be able to improve visual contrast sensitivity [20] and visual acuity [21]. And further studies indicated that in these DA-depleted animals, treatment with LDOPA produced transient recovery of abnormal ERG and VEP responses [18]. These facts implied that the above visual dysfunctions in these animals could be attributed to the depletion of DA in the retina. Visual dysfunctions of PD patients Visual dysfunctions involved in PD include impaired visual acuity [22], abnormal contrast sensitivity [13,23,24], deficits in color vision [25,26], abnormal motion perception [27], and visual hallucinations [28]. Contrast sensitivity is uniformly diminished in all frequencies in PD patients [13,29], and this can be correlated with the role of DA interplexiform cells on the receptive fields of horizontal cells coding for contrasts. The decrease of ERG b wave and delay of VEP latency in PD patients are identical to that observed in the DA-depleted animals [30]. Numerous evidences indicate that these abnormalities in visual capacity can be totally or partly attributed to retinal dysfunction [31], and can be reversed with the administration of L-DOPA [32]. In the healthy retina, treatment with DA blocker or D2 antagonist, mimics the same alternation seen in the PD patients [33]. Structural changes in the retina of PD patients Structural degeneration of the retina has been reported in PD. Post-mortem studies of PD patients indicated that TH immunoreactivity of dopaminergic neurons was reduced [4] and DA concentration in the retina was closely related to patients’ dosing conditions [34]. In addition, the decrease of DA innervations in the central area is obvious in PD patients [4]. These aspects do suggest a degenerative process in the dopaminergic neurons in the retina of PD patients. Besides, it was found that the mean retinal nerve fiber layer (RNFL) thickness, macular thickness and volume were significantly reduced in PD patients. And the reduction in RNFL thickness and macular thickness was inversely correlated with the severity of
Visual dysfunctions observed in PD patients are identical to those found in DA-depleted animals, thus suggesting a degenerative process of DA system in the retina of PD patients. Studies on the structural changes of the retina in PD patients have confirmed the degenerative process of dopaminergic neurons, including reductions in DA concentration, cell number, and DA innervation. As DA plays its role as modulator through direct synaptic contacts and the so-called ‘‘volume transmission” [36], which are the downstream effects after dopaminergic neuron degeneration in the visual network? An early electron microscope study on MPTPtreated rabbits [37] demonstrated some nuclear inclusions which indicate accelerated ageing in a number of amacrine cells and ganglion cells, but not the dopaminergic amacrines. This might due to the hyperactivity of the post-synaptic neurons induced by a decrease in DA metabolism. Also the reduction in RNFL thickness in PD patients might also be attributed to atrophy of the axons of ganglion cells in case of decreased DA input. These evidences confirm our hypothesis that the retina is a site of structural and functional change in Parkinson’s disease, retinal neurons and the visual network did undergo a degeneration process. However, previous studies on the retina of PD patients mostly focused on dopaminergic neurons, changes that involve other retinal neurons and the entire visual network need to be further addressed.
Issues that need to be addressed As DA exerts effects on the majority of retinal neurons, do actual alterations in other retinal neurons and reconstruction of visual network occur in PD patients due to the degeneration of dopaminergic neurons? DA is important in modulating the efficiency of other neurotransmitters such as glutamate, GABA and glycine in the retina [38]. Visual dysfunctions that results from DA depletion may involve long-term complex synaptic effects. As all visual dysfunctions must have their structural basis, they might be used as guidelines in exploring structural changes of the retina in PD patients. For example, the diminished contrast sensitivity observed in PD patients might be due to more strongly coupled horizontal cells and/or amacrines in the ‘‘absence” of DA [39]. Then studies on the gap-junction coupling of horizontal cells and/or amacrines in DA-depleted animals are needed to support the hypothesis. Methods in studying the morphological changes of various neurons and the remodeling of visual network in retinitis pigmentosa can also be used. Clinical motor and non-motor symptoms arise when 80% of dopaminergic neurons in substantia nigra were damaged. Whether the rate of dopaminergic neuron degeneration in the retina remains the same as that in substantia nigra is currently unknown. Increasing evidences indicate that visual dysfunction progresses with motor disability in PD and fluctuates in parallel with motor fluctuations [40]. In addition, further studies need to address the effects of L-DOPA on retinal structure and visual function. Postmortem studies have already showed that L-DOPA therapy could elevate DA concentration in the retina. Also, the effectiveness of L-DOPA on reversing visual dysfunctions has also been confirmed in PD patients and DA-depleted animals. However, the question remains: will L-DOPA therapy change the degeneration process of the retina induced by gradual loss of dopaminergic neurons? The therapy certainly does not have the ability to stop the degeneration
196
Y.M. Huang, Z.Q. Yin / Medical Hypotheses 76 (2011) 194–196
process, as a significant reduction in RNFL thickness was observed in L-DOPA treated PD patients [35]. Discussion The retina is an approachable part of the brain, with comparatively simple neuron cell types and synaptic organization. If adequate evidences confirmed our hypothesis that the retina in PD patients did undergo a degeneration process after gradual loss of dopaminergic neurons, we can further infer that the same degeneration might also occur in the brain. This will help explain the complicated motor and non-motor symptoms in PD that can not be explained by DA deficiency alone. If L-DOPA therapy can not stop the retina or brain from deteriorating, is there any other method that can inhibit this degeneration process? PD indeed appears to be a complex disease in which DA deficiency plays a major role, but it’s not the only relevant factor. Conflict of interest statement None declared. Acknowledgement This work was supported by the National Basic Research Program of China, Grant No. 2007CB512203. References [1] de Rijk MC, Breteler MM, Graveland GA, et al. Prevalence of Parkinson’s disease in the elderly: the Rotterdam study. Neurology 1995;45:2143–6. [2] Trenkwalder C, Schwarz J, Gebhard J, et al. Starnberg trial on epidemiology of Parkinsonism and hypertension in the elderly. Prevalence of Parkinson’s disease and related disorders assessed by a door-to-door survey of inhabitants older than 65 years. Arch Neurol 1995;52:1017–22. [3] Nussbaum RL, Ellis CE. Alzheimer’s disease and Parkinson’s disease. N Engl J Med 2003;348:1356–64. [4] Nguyen-Legros J. Functional neuroarchitecture of the retina: hypothesis on the dysfunction of retinal dopaminergic circuitry in Parkinson’s disease. Surg Radiol Anat 1988;10:137–44. [5] Archibald NK, Clarke MP, Mosimann UP, Burn DJ. The retina in Parkinson’s disease. Brain 2009;132:1128–45. [6] Jones BW, Marc RE. Retinal remodeling during retinal degeneration. Exp Eye Res 2005;81:123–37. [7] Witkovsky P, Schutte M. The organization of dopaminergic neurons in vertebrate retinas. Vis Neurosci 1991;7:113–24. [8] Ammermuller J, Kolb H. The organization of the turtle inner retina. I. On- and off-center pathways. J Comp Neurol 1995;358:1–34. [9] Witkovsky P, Nicholson C, Rice ME, Bohmaker K, Meller E. Extracellular dopamine concentration in the retina of the clawed frog, Xenopus laevis. Proc Natl Acad Sci USA 1993;90:5667–71. [10] Nguyen-Legros J, Simon A, Caille I, Bloch B. Immunocytochemical localization of dopamine D1 receptors in the retina of mammals. Vis Neurosci 1997;14:545–51. [11] Maguire G, Hamasaki DI. The retinal dopamine network alters the adaptational properties of retinal ganglion cells in the cat. J Neurophysiol 1994;72:730–41. [12] Mills SL, Xia XB, Hoshi H, et al. Dopaminergic modulation of tracer coupling in a ganglion-amacrine cell network. Vis Neurosci 2007;24:593–608. [13] Skrandies W, Gottlob I. Alterations of visual contrast sensitivity in Parkinson’s disease. Hum Neurobiol 1986;5:255–9. [14] Witkovsky P. Dopamine and retinal function. Doc Ophthalmol 2004;108:17–40.
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