[ZucchiniFlower]

Depression in Parkinson's disease: loss of dopamine and noradrenaline innervation in the limbic system

The reason for the high frequency of depression and anxiety in Parkinson's disease is poorly understood. Degeneration of neurotransmitter systems other than dopamine might play a specific role in the occurrence of these affective disorders. We used [11C]RTI-32 PET, an in vivo marker of both dopamine and noradrenaline transporter binding, to localize differences between depressed and non-depressed patients. We studied eight and 12 Parkinson's disease patients with and without a history of depression matched for age, disease duration and doses of antiparkinsonian medication. The depressed Parkinson's disease cohort had lower [11C]RTI-32 binding than non-depressed Parkinson's disease cases in the locus coeruleus and in several regions of the limbic system including the anterior cingulate cortex, the thalamus, the amygdala and the ventral striatum. Exploratory analyses revealed that the severity of anxiety in the Parkinson's disease patients was inversely correlated with the [11C]RTI-32 binding in most of these regions and apathy was inversely correlated with [11C]RTI-32 binding in the ventral striatum. These results suggest that depression and anxiety in Parkinson's disease might be associated with a specific loss of dopamine and noradrenaline innervation in the limbic system.

INTRO:


The frequency of depression in Parkinson's disease is ~40% (Brown and Jahanshahi, 1995Go; Cummings and Masterman, 1999Go). The rate of severe depression is twice that seen in other equivalently disabled patients (Rodin and Voshart, 1986Go). The natural history of depression in Parkinson's disease does not parallel the progression of physical symptoms, suggesting that it is an independent process that might affect vulnerable patients (Brown and Jahanshahi, 1995Go).

However, the pathophysiology of depression in Parkinson's disease remains obscure. Some authors constructed models including multiple factors (Brown and Jahanshahi, 1995Go), whereas others postulate that neurochemical abnormalities may explain depression in Parkinson's disease (Cummings and Masterman, 1999Go). While widespread dopamine deficiency is the main feature of Parkinson's disease, other neurotransmitter systems degenerate or are altered by the degenerative process, such as the noradrenergic and serotoninergic brainstem nuclei (Halliday et al., 1990Go). Several studies have suggested the involvement of these neurotransmitters in the pathogenesis of depression in Parkinson's disease, but no clear pattern has emerged (Brown and Jahanshahi, 1995Go; Tom and Cummings, 1998Go).

We used [11C]RTI-32 PET to study the role of catecholaminergic neurotransmission in the pathophysiology of depression in Parkinson's disease. [11C]RTI-32 binds with similar nanomolar affinities to the dopamine (DAT) and noradrenaline (NAT) membrane transporters but with far lower affinity to the serotonin transporter (Carroll et al., 1995Go). We compared the binding of this tracer in depressed and non-depressed Parkinson's disease patients who had similar age, disease severity and doses of antiparkinsonian medication....

DISCUSSION:


Depression in Parkinson's disease patients is associated with a reduction of [11C]RTI-32 binding in several limbic regions. In addition, there is an inverse relationship between the binding of [11C]RTI-32 in these regions and the severity of anxiety and mood disorders in these patients.

These abnormalities seem specific for depression in Parkinson's disease since we matched depressed and non-depressed Parkinson's disease patients for demography and locomotor disability, including age, disease duration, UPDRS-motor ‘off’ score and doses of antiparkinsonian medication. Accordingly, we found no difference between the two groups of patients for [11C]RTI-32 uptake in the striatum or the substantia nigra.

Differences between depressed and non-depressed Parkinson's disease were observed using both an ROI analysis and voxel-based SPM. The slight differences between the results obtained using these approaches are explained by methodological considerations. For example, the CingA was not included in the masked SPM comparison in order to restrict the analysis to subcortical and brainstem areas and gain statistical power.

The decrease of [11C]RTI-32 BP reflects a loss of catecholaminergic innervation in the corresponding regions of the brain. [11C]RTI-32 binds mainly to DAT in the striatum (Carroll et al., 1995Go; Wilson et al., 1996Go), and the binding of this tracer is markedly reduced in the putamen of patients with Parkinson's disease (Guttman et al., 1997Go). We also found a reduction of [11C]RTI-32 binding in the substantia nigra of Parkinson's disease patients. Thus, it is possible to demonstrate loss of dopaminergic cell function directly in the substantia nigra (Rakshi et al., 1999Go), since DAT is present on the dendrites of dopaminergic neurons (Nirenberg et al., 1996Go).

[11C]RTI-32 has nanomolar affinity for the NAT, whereas it has a low affinity for the serotonin transporter (Carroll et al., 1995Go). Therefore, part of the decrease of [11C]RTI-32 binding observed in depressed Parkinson's disease patients could be related to loss of noradrenergic terminals. This is supported by the finding that [11C]RTI-32 binding was reduced in the locus coeruleus and in the thalamus. In addition, the locus coeruleus sends noradrenergic projections to the frontal cortex, the amygdala and the ventral striatum (Ressler and Nemeroff, 1999Go). Altogether, this suggests that the decrease of [11C]RTI-32 binding observed in the depressed Parkinson's disease patients corresponds to the loss of both dopamine and noradrenaline projections. Alternatively, the downregulation of DAT and NAT binding might be secondary to reduced release of endogenous ligand in these synapses (Metzger et al., 2002Go). Nevertheless, in Parkinson's disease patients, we suspect that loss of catecholaminergic terminals (Paulus and Jellinger, 1991Go) plays a much more dominant role in the reduction of [11C]RTI-32 binding observed in this study than any pharmacodynamic regulation of the transporter density on the remaining membranes.

Dopamine interactions with the limbic system are probably involved in stress and depression (Cabib and Puglisi-Allegra, 1996Go). In Parkinson's disease, pessimism measured using the harm-avoidance personality score was reported to be correlated with [18F]Dopa uptake in the right caudate nucleus (Kaasinen et al., 2001Go). Mood fluctuations can occur independently from motor fluctuations (Maricle et al., 1995Go), implicating involvement of ventral rather than dorsal brain circuitary, and are often improved by antiparkinsonian medication (Czernecki et al., 2002Go).

Parkinsonian patients with major depression do not feel euphoria following administration of the dopamine-releasing agent methylphenidate. This has been attributed to degeneration of the dopaminergic innervation of the limbic system (Cantello et al., 1989Go).

The role of noradrenaline in affective disorders is widely documented (Ressler and Nemeroff, 1999Go; Sullivan et al., 1999Go). A loss of pigmented neurons has been found in the locus coeruleus of suicide victims (Arango et al., 1996Go), and the level of NAT is reduced post-mortem in the locus coeruleus of patients with major depression (Klimek et al., 1997Go).

The degeneration of the locus coeruleus occurring in Parkinson's disease (Paulus and Jellinger, 1991Go) might play a role in mood changes in these patients (Zweig et al., 1993Go). This is supported here by the lower [11C]RTI-32 binding found in the locus coeruleus of depressed compared with non-depressed patients. In addition, the negative correlation found between locus coeruleus [11C]RTI-32 binding and severity of anxiety in Parkinson's disease supports a direct role for noradrenaline in the pathophysiology of anxiety in Parkinson's disease.

It is striking that the reduction of catecholaminergic innervation in depressed Parkinson's disease patients occurs in regions thought to comprise the emotional circuits of the brain. Indeed, the amygdala, mediodorsal thalamus, ventral striatum and CingA belong to the limbic system and have been implicated as dysfunctional regions in mood disorders (Drevets, 1998Go).

The amygdala is a key structure for emotional processing in humans (LeDoux, 2000Go). Functional abnormalities in the amygdala correlate with severity of endogenous depression (Drevets, 1998Go), and the amygdala mediates fear processing and anxiety (LeDoux, 2000Go). The amygdala connects with locus coeruleus and receives a noradrenergic and dopaminergic innervation (Fallon et al., 1978Go; Fudge and Emiliano, 2003Go) which is reduced in Parkinson's disease (Moore, 2003Go).

In addition, it has been reported in a post-mortem study that Parkinson's disease patients have up to a 20% reduction of amygdala volume and that this structure contains Lewy bodies (Harding et al., 2002Go).

In our study, [11C]RTI-32 binding was significantly reduced in the right amygdala of depressed Parkinson's disease patients and the anxiety score was negatively correlated with bilateral amygdala [11C]RTI-32 binding. The loss of noradrenaline and dopamine in the amygdala is likely to play a role in generating affective symptoms in Parkinson's disease.

The amygdala has connections with the CingA (LeDoux, 2000Go) where, with an ROI analysis, we found a reduction of [11C]RTI-32 binding in the depressed compared with the non-depressed Parkinson's disease patients. The CingA is part of the limbic system and involved in many cognitive and emotional processes (Paus et al., 1993Go; Drevets, 1998Go). In addition, the CingA receives a strong dopaminergic and noradrenergic innervation (Williams and Goldman-Rakic, 1993Go). Two PET studies have revealed CingA hypometabolism associated with depression in Parkinson's disease (Ring et al., 1994Go; Mentis et al., 2002Go). Our results suggest that such dysfunction of CingA in depressed Parkinson's disease might be related to a specific loss of catecholaminergic projections.

Noradrenergic projections to the thalamus target the medial and intralaminar subnuclei (Oke et al., 1997Go), where we found a significant loss of [11C]RTI-32 binding in depressed compared with non-depressed Parkinson's disease patients. The role of the thalamus in depression is unclear. However, a recent study showed that depression and anxiety induced by {alpha}-methylparatyrosine, a tyrosine hydroxylase inhibitor, was associated with a marked reduction of glucose metabolism in the thalamus (Bremner et al., 2003Go). The role of the thalamus in affective disorders might be related to its involvement in arousal. Indeed, anxiety is associated with changes in vigilance that implicate the same thalamo-cortical interactions which are under the control of the noradrenergic innervation originating in the locus coeruleus (Ressler and Nemeroff, 1999Go; David Johnson, 2003Go). Accordingly, the correlation between anxiety and [11C]RTI-32 binding in the thalamus in these patients suggests that impaired noradrenergic modulation of thalamic activity plays a role in the generation of anxiety in Parkinson's disease.

Finally, depressed Parkinson's disease patients showed a relative reduction of [11C]RTI-32 binding in the ventral striatum, which is involved in emotional processing via its connections with frontal limbic regions (Nakano, 2000Go). The dopaminergic system is less affected in the ventral striatum than more dorsal regions in Parkinson's disease (Kish et al., 1988Go), but receives most of the noradrenergic afferents of the striatum (Nicola and Malenka, 1998Go).

In non-parkinsonian depressed patients, a single photon emission computed tomography (SPECT) study using [123I]ß-CIT reported an increase of tracer uptake in the striatum compared with controls (Laasonen-Balk et al., 1999Go). However, [123I]ß-CIT also binds to the serotonin transporter (Carroll et al., 1995Go) and increased uptake may reflect serotonin transporter upregulation in depression. Conversely, a recent study reported a decrease of [11C]RTI-32 binding in the ventral striatum of depressed subjects (Meyer et al., 2001Go). In line with this result, we found a reduction of the [11C]RTI-32 binding in the left ventral striatum of the depressed Parkinson's disease patients. Interestingly, we found that [11C]RTI-32 binding in the ventral striatum was inversely correlated with the degree of apathy and the intensity of depression in the patients.

It seems that the dopaminergic and noradrenergic innervation of the ventral striatum is involved in both endogenous and Parkinson's disease depression, and, might specifically play a role in apathy which is a major feature of depression. Interestingly, L-Dopa treatment might improve motivation in some patients with Parkinson's disease (Czernecki et al., 2002Go).

In conclusion, our results suggest that depression in Parkinson's disease is associated with a specific loss of dopamine and noradrenaline innervation of cortical and subcortical components of the limbic system. These results might help in understanding the functional anatomy of depression in Parkinson's disease and have therapeutic implications.

These results might be replaced in the more general context of the relationships between ageing, depression and catecholamines. Briefly, the reduction of catecholaminergic innervation that occurs in the cortical limbic structures might participate in the loss of cognitive abilities such as flexibility, attention or executive functions that is known to occur with ageing (Nieoullon, 2002Go). On the same lines, it is considered that increased anxiety found in elderly people might be related to the loss of dopaminergic and noradrenergic innervation, especially in the amygdala (Gareri et al., 2002Go). Therefore, some authors have suggested that pre-depressive and pre-dementia states that are sometimes observed with ageing have underlying pathophysiology in common with Parkinson's disease (Gareri et al., 2002Go).

http://brain.oxfordjournals.org/cgi/...128/6/1314#top

[ZucchiniFlower]

There is higher depression in people with postural and gait disabilities. And akinesia and rigidity predisposes one to depression.

Diagnostic aspects of early Parkinson’s disease

Thomas Müller1 Contact Information, Gerd Fuchs2, Matthias Hahne3, Wolfgang Klein4 and Michael Schwarz5

Journal of Neurology
Publisher Steinkopff
ISSN 0340-5354 (Print) 1432-1459 (Online)
Issue Volume 253, Supplement 4 / September, 2006

Abstract

Insidious onset of mild, unspecific, sensitive, vegetative, psychopathological, cognitive and perceptive disturbances, i. e., visual and olfactory dysfunction, with a resulting change of personal behavior, i. e., reduced stress tolerance, precede the initially intermittently occurring motor symptoms in patients with Parkinson’s disease (PD).

Novel neuropathological findings suggest an expansion pattern of the neurodegenerative process beyond the nigral dopaminergic neurons with the initial event located outside the brain.

This underlines the clinical concept of an initial premotor phase, which starts in nondopaminergic areas in PD. Moreover a more global general understanding of chronic neurodegeneration enables the performance of clinical trials on neuroprotection, since there is increasing evidence that diagnosis of PD at the threshold of onset of motor symptoms or cognitive symptoms in Alzheimer’s disease is too late. Such an earlier diagnosis of chronic neurodegeneration will allow a more convincing demonstration of the efficacy of a neuroprotective or disease modifying compound. It will also support the concept of a clinically effective pharmacological intervention on a disease process, which is also more and more demanded by the health authorities for drug approval.

http://www.springerlink.com/content/...3/fulltext.pdf

[Heidi L]

Science!!! Thank you for this.

This is one of my goals- to get the medical establishment to consider depression and sleep disorders as preliminary symptoms of degenerative neurological diseases, and to facilitate the production of simple tests to rule out such pathology prior to the designation of social/psychological diagnoses, which merely allow the disease to progress.

Referring the other threads, rather than being handed antidepressants like candy and sent on ones way, perhaps something like early nicotine treatment could actually avert the later symptoms of PD.

Oh wait, that's not patentable and there's no permanent revenue stream. Never mind....

[ZucchiniFlower]

I agree, Heidi. Seems that taking azilect early can delay progression. I know they need more studies, but it sure seems promising.