Ehringer and Hornykiewicz (1960) first reported that Parkinson's disease (PD) was characterized by profound loss of striatal dopamine (DA). These findings served as the basis of the subsequent demonstration of the effectiveness of the DA precursor, l-DOPA in improving motor performance in PD patients. With blinkers on, the PD research community then focused almost exclusively on DA deficiency and its effects on striatal function. Virtually all of the currently available therapies are based on augmenting dopaminergic function. While these are of unquestionable benefit to patients, they are far from ideal. The motor response to l-DOPA and DA agonist treatments may be incomplete, accompanied by significant adverse effects, or variable in nature. There are motor symptoms, such as tremor and freezing of gait, which are refractory to current therapies. There is also increasing recognition of the importance of a wide range of non-motor symptoms which include autonomic impairment, sleep disorders, mood disorders, and cognitive impairment; these are in general poorly responsive to l-DOPA treatment or other therapies, and produce great disability. A narrow focus on dopaminergic mechanisms has largely carried the field to the present day, but it is time to remove the blinkers and look beyond that dopamine-centric view of PD.
In the current issue, Pifl et al. (2013) have returned to one of the oldest outstanding questions in PD, the role of the catecholamine noradrenaline (NA). DA is, of course, the immediate precursor of NA, a conversion mediated by the enzyme DA beta hydroxylase. Indeed, this precursor function was for many years believed to be primary role of DA, which was itself thought to be ‘without any interest because of its low physiological activity,’ as Arvid Carrlson noted in his Nobel lecture on the discovery of the neurotransmitter functions of DA. The primary source of NA in the forebrain is the neurons of the locus coeruleus. The projections of this nucleus are widespread; they include the thalamus, hypothalamus, amygdala, hippocampus, and extensive projections to neocortex (Delaville et al. 2011).
Degeneration of the locus coeruleus structure in human PD is well documented (for review, see Delaville et al. 2011). Recent studies by Braak and colleagues suggest that loss of NA cells may be an early event, preceding destruction of DA and other monoaminergic systems (Braak et al. 2004). The loss of LC neurons would be expected to produce impairment of NA transmission in the target regions of the nucleus, but only recently has evidence of the extent and distributions of this disruption emerged. Pifl et al. (2012) examined NA content in the thalamus from postmortem brains of PD patients and found approximately 90% depletion of NA in the motor regions of the thalamus (ventroanterior and ventrolateral). Lesser, but still substantial degrees of loss were observed in the sensory (venteroposterior) nuclei. These findings were thought to be particularly relevant because of evidence that NA can have important effects on patterns of neuronal firing in the thalamus. A limitation of this study, however, is that all of the brains studied were from patients with advanced disease, and little data on their clinical state near the time of death were available.
In the current issue, these authors have expanded on the human postmortem studies by examining monoaminergic levels in the thalamus in MPTP-treated non-human primates. The samples used here are from animals with careful clinical characterization, and represent a range of severity from asymptomatic or ‘recovered’ to severe parkinsonism. A key finding is that NA depletion in the thalamus appeared to track the severity of motor symptoms. All of the MPTP treated animals had marked loss of striatal DA. The mildly and severely parkinsonian monkeys had significant deficits in NA levels within the ventrolateral thalamus (~50% loss), and severely parkinsonian monkeys had significant NA loss which extended to the ventroanterior thalamic region (~65% loss). In contrast, the asymptomatic and recovered animals had normal NA content in the thalamus. These data support the hypothesis that thalamic NA loss is required for expression of motor parkinsonism in a dopamine depleted state (see Fig. 1).
An obvious limitation of this study is the use of the MPTP lesioned animals as models of human PD at different stages of progression. Interestingly, thalamic NA deficits were more widespread in human PD compared with the MPTP-treated monkeys, with loss observed in both motor and non-motor regions of the thalamus. These differences may be an indication of the limitations of the MPTP model in accurately reproducing the temporal and spatial characteristics of the pathology of human PD.
A broader conceptual issue in the interpretation of both the human and non-human primate studies is that these are fundamentally correlative in nature. While it is reasonable to hypothesize that loss of NA in the thalamus may be important for the pathogenesis of parkinsonism, these descriptive data do not establish causality. There are also likely losses of NA in other regions, such as neocortex, which may be important. In addition, it is possible that the changes in NA may simply be a proxy for other alterations in brain chemistry or function.
Mechanistic studies do provide a framework for understanding the potential effects of thalamic NA deficiency. NA has been shown to alter the activity of neurons, acting to enhance ‘signal to noise’ ratios (Berridge and Waterhouse 2003). Applying NA to neurons in the thalamus and other brain regions serves to reduce spontaneous activity (‘noise’), while enhancing neuronal responses to directed synaptic input (‘signal’). Thus, the effect of loss of thalamic NA may be to diminish the accuracy of signal transfer. For example, MPTP-treated primates show reduced specificity of responses to sensory input in the ventroanterior and ventrolateral motor thalamic regions (Pessiglione et al. 2005). In both PD patients and in preclinical models, parkinsonism is associated with increased thalamic neuronal bursting activity, pathological oscillations, and impaired thalamic receptive fields (Galvan and Wichmann 2008).
Reduced NA levels could also contribute to the development of non- l-DOPA-responsive motor symptoms in PD patients (Delaville et al. 2011). Resting tremor is not improved by l-DOPA treatment and is associated with enhanced thalamic oscillatory activity. Other pathophysiological activity in the thalamus, via afferent connections to supplementary and pre-supplementary motor cortices, may underlie the development of bradykinesia and rigidity. It is also logical to predict that inappropriate ventroanterior/ventrolateral thalamic signal transfer would exacerbate or cause the development of other motor symptoms, such as freezing, and gait and balance problems. Interestingly, these symptoms are primarily evident in later stages of PD and would be roughly equivalent to a severely parkinsonian MPTP-treated primate as in this study.
Although not directly addressed in this study, extra-thalamic NA may be important in the pathogenesis of PD symptomatology. Because of NA's roles in arousal, attention, cognition and mood, deficits of NA in these regions could contribute to depression, dementia, and other impairments observed in PD patients. In support, several selective NA reuptake inhibitors have proven as effective as serotonergic drugs in the treatment of depression in PD patients. Furthermore, thalamic NA binding was reduced in depressed PD patients and was inversely correlated with the severity of anxiety (Remy et al. 2005). Thus, thalamic noradrenergic deficit may be a viable contributor to the progression of both motor and non-motor symptomatology in PD.
The question remains: Does the thalamic defect in NA dysfunction lead us to new insights regarding the treatment of PD? Of course, l-DOPA serves as a precursor for both DA and NA, and thus there may already be a therapy active on both systems. It has been argued that such a combined effect is responsible for the apparent superiority of l-DOPA over other DA augmentation strategies. However, only a portion of l-DOPA is converted into NA and is unknown whether it can adequately restore thalamic NA levels. Indeed, evidence suggests that l-DOPA can usurp NA function, leading to deficits in some brain regions (Nicholas et al. 2008). Studies with agents such as idazoxan, an antagonist of α2AR autoreceptors which should enhance NA release, have not revealed evidence for a direct motor enhancing effect but may synergize with l-DOPA (for review, see Delaville et al. 2011). On the whole, the available data support the hypothesis that replacement of thalamic NA may be beneficial in PD, but this idea still awaits rigorous validation in model systems and PD patients.
Much as Hornykiewicz and his colleagues pushed PD research into a new direction in the 1960s, these new studies reinforce the idea that it is time to ‘take the blinkers off’ and look beyond striatal DA in the search for better treatments for PD patients. A broader view is almost certain to lead us to new discoveries.