Non-depressed Parkinson's Disease Patients Research Articles

Abnormal amygdala function in Parkinson's disease patients and its relationship to depression

Depression is a common occurrence in patients with Parkinson's disease (PD). Thus, there may be a common neural mechanism underlying the two diseases. Lewy body accumulation in specific brain areas of PD patients may damage emotion-related functions, leading to depression. Among these areas, the amygdala may present with the earliest to be damaged in PD. However, it is still unclear whether amygdala structural and functional changes are related to depression in PD. We enrolled 19 depressed PD patients, 19 non-depressed PD patients, and 28 normal control subjects. Clinical assessment, including the Unified Parkinson's Disease Rating Scale, the Hamilton Rating Scale for Depression, and the Mini-Mental State Examination, was carried out on all the patients. Structural and resting-state functional brain images were also acquired to assess volumetric and functional changes of the amygdala in the patients. Results showed that although there is no significant volume change, left amygdala activity increased in the PD group compared with the normal control group, and it correlated with Hamilton Rating Scale for Depression scores. Furthermore, functional connectivity between the right amygdala and fronto-parietal areas was found to be decreased in the depressed PD patients compared with non-depressed PD patients. These results suggest that abnormal amygdala function may underlie the occurrence of depression in PD.

Transcranial midbrain sonography and depressive symptoms in patients with Parkinson's disease.

Transcranial sonography (TCS) appeared to be a promising marker associated with depression: hypo/anechogenicity of the brainstem raphe (BR) was found in 50-70 % of patients with unipolar depression, in 40-60 % of depressed patients with Parkinson's disease (PD), but also in 8-28 % of healthy controls. Our study included 120 consecutive PD outpatients. Abnormal BR echogenicity was found in 51 (43 %), while normal findings were present in 67 PD patients (57 %). Patients with abnormal BR echogenicity had higher scores on the Montgomery-Asberg Depression Rating Scale (MADRS) items of apparent sadness (p = 0.03), reported sadness (p = 0.01), and pessimistic thoughts (p = 0.049), when compared to those with normal BR. In the second part of the study, previously suggested cut-off value at 14/15 on the MADRS was used to dichotomize patients into depressed (dPD) (46 patients; 39 %) and non-depressed PD patients (ndPD) (72 patients; 61 %). Abnormal TCS BR findings were obtained in 27 dPD (58.7 %) and in only 24 ndPD patients (33.3 %) (p = 0.007): the risk that PD patients with the TCS BR abnormality would display depressive symptoms was about 3.5 times higher when compared to PD patients with intact BR, controlling for the effect of motor difficulties (cross-odds ratio; OR = 3.48). Therefore, at least in a subgroup of dPD patients, TCS of the midbrain midline structure may potentially be a useful tool for depressive symptoms prediction.

Abnormal functional connectivity of the amygdala is associated with depression in Parkinson's disease.

Depressive symptoms are common in Parkinson's disease (PD), but the pathophysiology and neural basis underlying depression in PD is not well understood. Abnormal functional connectivity of the amygdala with various cortical and subcortical areas has been observed in major depressive disorder, indicating that dysfunction of the corticolimbic network may be involved in the pathogenesis of major depressive disorder. However, little is known about alterations of amygdala functional connectivity in depressed PD patients. In the present study, 20 depressed PD patients, 40 nondepressed PD patients, and 43 matched healthy controls underwent neuropsychological tests and resting-state functional MRI scanning. Between-group differences in amygdala functional connectivity network were examined using t tests. Compared to the nondepressed PD patients, depressed PD patients showed increased left amygdala functional connectivity with the bilateral mediodorsal thalamus, right amygdala functional connectivity with the left superior temporal gyrus, and left calcarine gyrus. Compared to the healthy controls, the depressed PD group also showed increased left amygdala functional connectivity with the bilateral mediodorsal thalamus, but decreased left amygdala functional connectivity with the left putamen, left inferior frontal gyrus, and the right cerebellum, as well as decreased right amygdala functional connectivity with the left inferior orbitofrontal gyrus, the left gyrus rectus, and the right putamen. The increased connectivity between limbic regions and decreased connectivity between the corticolimbic networks may reflect impaired high-order cortical regulatory effects on the emotion-related limbic areas, which may lead to mood dysregulation. Our study should advance the understanding of neural mechanisms underlying depression in PD.

Disrupted white matter integrity in depressed versus non-depressed Parkinson's disease patients: A tract-based spatial statistics study

Depression is a common occurrence in patients with Parkinson's disease (PD), however, its pathophysiology still remains unclear. With increasing evidence suggesting that depression is a disconnection syndrome, we hypothesized that depression in PD is caused by degenerated fiber connections in the brain. We examined whole brain white matter integrity in 15 depressed PD patients and 15 non-depressed PD patients. All the patients were assessed with the Unified Parkinson's Disease Rating Scale, the Hamilton Rating Scale for Depression, and the Mini-Mental State Examination. White matter difference between the two groups and its correlation with disease severity was calculated. In depressed PD patients, decreased fractional anisotropy was found in the left uncinate fasciculus, superior longitudinal fasciculus, anterior thalamic radiation, forceps minor, and the inferior longitudinal fasciculus. Fractional anisotropy in the left deep temporal cortex was negatively correlated with severity of depression (r=−0.671, p=0.034). Our results suggest that disrupted fiber connections in the anterior part of the left hemisphere may contribute to depression in PD patients.

Oscillatory subthalamic nucleus activity is modulated by dopamine during emotional processing in Parkinson's disease

Dopaminergic denervation in Parkinson's disease (PD) leads to motor deficits but also depression, lack of motivation and apathy. These symptoms can be reversed by dopaminergic treatment, which may even lead to an increased hedonic tone in some patients with PD. Here, we tested the effects of dopamine on emotional processing as indexed by changes in local field potential (LFP) activity of the subthalamic nucleus (STN) in 28 PD patients undergoing deep brain stimulation. LFP activity from the STN was recorded after the administration of levodopa (ON group) or after overnight withdrawal of medication (OFF group) during presentation of an emotional picture-viewing task. Neutral and emotionally arousing pleasant and unpleasant stimuli were chosen from the International Affective Picture System. We found a double dissociation of the alpha band response depending on dopamine state and stimulus valence: dopamine enhanced the processing of pleasant stimuli, while activation during unpleasant stimuli was reduced, as indexed by the degree of desynchronization in the alpha frequency band. This pattern was reversed in the OFF state and more pronounced in the subgroup of non-depressed PD patients. Further, we found an early gamma band increase with unpleasant stimuli that occurred when ON but not OFF medication and was correlated with stimulus arousal. The late STN alpha band decrease is thought to represent active processing of sensory information. Our findings support the idea that dopamine enhances approach-related processes during late stimulus evaluation in PD. The early gamma band response may represent local encoding of increased attention, which varies as a function of stimulus arousal.

Altered Spontaneous Brain Activity in Patients with Parkinson’s Disease Accompanied by Depressive Symptoms, as Revealed by Regional Homogeneity and Functional Connectivity in the Prefrontal-Limbic System

As patients with Parkinson’s disease (PD) are at high risk for comorbid depression, it is hypothesized that these two diseases are sharing common pathogenic pathways. Using regional homogeneity (ReHo) and functional connectivity approaches, we characterized human regional brain activity at resting state to examine specific brain networks in patients with PD and those with PD and depression (PDD). This study comprised 41 PD human patients and 25 normal human subjects. The patients completed the Hamilton Depression Rating Scale and were further divided into two groups: patients with depressive symptoms and non-depressed PD patients (nD-PD). Compared with the non-depressed patients, those with depressive symptoms exhibited significantly increased regional activity in the left middle frontal gyrus and right inferior frontal gyrus, and decreased ReHo in the left amygdala and bilateral lingual gyrus. Brain network connectivity analysis revealed decreased functional connectivity within the prefrontal-limbic system and increased functional connectivity in the prefrontal cortex and lingual gyrus in PDD compared with the nD-PD group. In summary, the findings showed regional brain activity alterations and disruption of the mood regulation network in PDD patients. The pathogenesis of PDD may be attributed to abnormal neural activity in multiple brain regions.

Pharmacologic Treatment of Anxiety Disorders in Parkinson Disease

Neither best practices nor an evidence base for the pharmacologic treatment of anxiety in Parkinson disease (PD) has been established. This study investigated pharmacologic treatment of anxiety disorders in idiopathic PD and the associated clinical features. Cross-sectional. Three community-based movement disorder neurology practices. 250 subjects with PD. Anxiety disorder diagnoses were established by consensus using a panel of six psychiatrists with expertise in geriatric psychiatry and movement disorders. Current medications were provided by the treating neurologists at the time of interview. Among subjects with anxiety disorders only, 53% were untreated with medications. When anxious subjects with comorbid depressive disorders were included, 70.8% were on medications effective for treatment of anxiety. Subjects with anxiety and comorbid depressive disorders were more likely to be treated for their psychiatric disturbances than subjects with anxiety disorders alone (odds ratio: 8.33), as were subjects with comorbid motor fluctuations (odds ratio: 3.65). There were no differences in the types of anti-anxiety medications used in regard to the presence of depression or motor fluctuations. These findings suggest that over half of nondepressed PD patients with clinically significant anxiety are untreated with medication. A better understanding of the role of clinical features associated with anxiety in PD, such as depression and motor fluctuations, may improve the recognition and treatment of anxiety disorders in this population.

Daytime Sleepiness is Associated with Falls in Parkinson's Disease

Falls are frequent in Parkinson's disease (PD), and may be influenced by daytime sleepiness. We reviewed the records of 120 men with PD. Mean Epworth Sleepiness Scale (ESS) values were significantly different between non-fallers and fallers (6.0 vs. 9.7, p < 0.01). In multivariate analysis, ESS remained significantly associated with falls (OR 1.2, 95% CI 1.1-1.4, p = 0.02), along with cognitive impairment (OR 4.4 95% CI 1.0-18.7, p = 0.04) and postural instability/gait dysfunction (OR 1.6 95% CI 1.0-2.4, p = 0.03) in non-depressed patients. In conclusion, non-depressed PD patients are 20% more likely to fall for every one unit increase in the ESS measure of sleepiness.

The impact of depression on survival of Parkinson's disease patients: a five-year study

OBJECTIVE: The aim of this study is to evaluate the survival rate in a cohort of Parkinson's disease patients with and without depression. METHODS: A total of 53 Parkinson's disease subjects were followed up from 2003-2008 and 21 were diagnosed as depressed. Mean time of follow up was 3.8 (SD 95% = 1.5) years for all the sample and there was no significant difference in mean time of follow up between depressed and nondepressed Parkinson's disease patients. Survival curves rates were fitted using the Kaplan-Meier method. In order to compare survival probabilities according to the selected covariables the Log-Rank test was used. Multivariate analysis with Cox regression was performed aiming at estimating the effect of predictive covariables on the survival. RESULTS: The cumulative global survival of this sample was 83% with nine deaths at the end of the study - five in the depressed and four in the nondepressed group, and 55.6% died in the first year of observation, and none died at the fourth and fifth year of follow up. CONCLUSION: Our finding point toward incremental death risk in depressed Parkinson's disease patients.

Apathy in Nondemented and Nondepressed Parkinson's Disease Patients: A PET Study (P03.122)

Apathy in Nondemented and Nondepressed Parkinson's Disease Patients: A PET Study (P03.122)

Apathy, but not depression, reflects inefficient cognitive strategies in Parkinson's disease.

BackgroundThe relationship between apathy, depression and cognitive impairment in Parkinson's disease (PD) is still controversial. The objective of this study is to investigate whether apathy and depression are associated with inefficient cognitive strategies in PD.MethodsIn this prospective clinical cohort study conducted in a university-based clinical and research movement disorders center we studied 48 PD patients. Based on clinical evaluation, they were classified in two groups: PD with apathy (PD-A group, n = 23) and PD without apathy (PD-NA group, n = 25). Patients received clinical and neuropsychological evaluations. The clinical evaluation included: Apathy Evaluation Scale-patient version, Hamilton Depression Rating Scale-17 items, the Unified Parkinson's Disease Rating Scale and the Hoehn and Yahr staging system; the neuropsychological evaluation explored speed information processing, attention, working memory, executive function, learning abilities and memory, which included several measures of recall (immediate free, short delay free, long delay free and cued, and total recall).FindingsPD-A and PD-NA groups did not differ in age, disease duration, treatment, and motor condition, but differed in recall (p<0.001) and executive tasks (p<0.001). Immediate free recall had the highest predictive value for apathy (F = 10.94; p = 0.002). Depression and apathy had a weak correlation (Pearson index = 0.3; p<0.07), with three items of the depression scale correlating with apathy (Pearson index between .3 and.4; p<0.04). The depressed and non-depressed PD patients within the non-apathetic group did not differ.ConclusionApathy, but not depression, is associated with deficit in implementing efficient cognitive strategies. As the implementation of efficient strategies relies on the fronto-striatal circuit, we conclude that apathy, unlike depression, is an early expression of executive impairment in PD.

The Parkinsonian Personality and Concomitant Depression

Parkinson's disease (PD) has been associated with a distinctive parkinsonian personality, characterized by conscientiousness, punctuality, industriousness, and reduced novelty-seeking, as compared with healthy elderly persons. Similar traits are identified in relation to depression. The objective of the study was to elucidate the relationship between the parkinsonian personality and depression. Thirty-two depressed and 86 nondepressed PD patients and 30 healthy control subjects completed the NEO-Personality Inventory Revised Short Version. PD patients with depression displayed a distinct personality profile, with increased Neuroticism and reduced Extroversion, as compared with nondepressed PD patients and control subjects. It seems plausible that a subgroup of PD patients possesses a distinct personality profile that renders them sensitive to development of depression, although the reverse might also be possible.

The Role of Dopamine Agonists in the Treatment of Depression in Patients with Parkinsonʼs Disease

Depressive disorders as well as depressive symptoms are common in Parkinson's disease (PD) and an important factor affecting quality of life. Treatment of depressive symptoms not only improves mood but is also associated with improvement of motor symptoms, disability and cognitive symptoms. Currently, dopamine agonists are being suggested as an alternative to antidepressants for the treatment of depression in PD. The aim of this article is to systematically review the efficacy of dopamine agonists in the treatment of depression in PD. Since 1983, 19 studies have reported on the effects of dopamine agonists on depressive disorder, depressive symptoms or mood in PD. To date, no double-blind, placebo-controlled, randomized controlled trial of the treatment of major depressive disorder in PD with a dopamine agonist has been conducted. Studies of the effects of treatment with dopamine agonists on depressive symptoms in PD, or on mood in non-depressed PD patients, have yielded inconclusive results. Most studies are not designed to test effects on mood and are limited by methodological flaws. It can be concluded that, although the preliminary evidence of the effects on mood and depression in PD is interesting and in need of further study, there is as yet insufficient evidence to recommend dopamine agonists in the treatment of either depressive disorder or depressive symptoms in patients with PD. Treatment of depressive disorder and clinically relevant depressive symptoms should be based on pharmacological or non-pharmacological interventions with known efficacy in this population, such as citalopram, nortriptyline, desipramine or cognitive behavioural therapy. This strategy has the additional advantage of enabling the clinician to treat depressive symptoms independently of motor symptoms, thus avoiding potential complications of dopaminergic therapy.

Dopaminergic modulation of the default mode network in Parkinson's disease

Default mode network (DMN) is characterized by a deactivation of several cortical areas (including medial prefrontal cortex and posterior cingulate cortex) during goal-directed experimental tasks. Few findings are reported on DMN and the involvement of dopaminergic medication on this network in Parkinson's disease (PD). To evaluate the effect of levodopa on DMN deactivation, we conducted a randomized, crossover, placebo-controlled experiment consisting of two fMRI assessments in fourteen non-demented, non-depressed PD patients compared to thirteen healthy volunteers. They received either acute doses of levodopa or placebo in two fMRI sessions. Brain deactivation was evaluated during a facial emotion recognition task. While the control subjects showed a classical brain deactivation pattern during the emotional task, the PD patients taking placebo only deactivated the ventral medial prefrontal cortex. Patients failed to deactivate the posterior midline and lateral parts of DMN network. After levodopa administration, this network was restored conjointly with the improvement of motor dysfunction in PD patients. The levodopa effect on DMN is probably the consequence of a beneficial dopamine (DA) medication effect which leads to a fine tuning of the dopamine level in the motor part of striatum, resulting to a global improvement of physical state of PD patients and consequently an increased attentional resource to external stimuli. The absence of medial prefrontal deactivation impairment may suggest a preserved mesocortical DA system in these patients.

Higher dopamine transporter density in Parkinson’s disease patients with depression

Depression is a frequent non-motor symptom in Parkinson's disease (PD) with increasing rates with the progression of the disease. Molecular imaging studies have shown a reduction of dopamine transporter (DAT) density in depressed PD patients (dPD); however, DAT role in the pathophysiology of PD depression is not clear since clinical matching was inappropriate and DAT reduction could be attributed to PD severity. To further examine the role of DAT in PD depression, this study compared thoroughly matched depressed vs. non-depressed PD patients (ndPD). Twenty PD patients (n = 10 ndPD; n = 10 dPD) matched for age and disease severity were submitted to brain SPECT imaging with [(99m)Tc]-TRODAT-1, a DAT radioligand. DAT-binding potential was calculated using regions of interest bilaterally drawn in the striatum, caudate, and putamen. Depression was defined according to Beck Depression Inventory (BDI; cut-off >18). Mean BDI scores were higher in dPD (25.0 +/- 5.6) than in ndPD patients (8.0 +/- 1.9, p < 0.0001). DAT density was greater on dPD especially in the left caudate (dPD 0.87 +/- 0.19 vs. ndDP 0.69 +/- 0.18, p = 0.02) and right putamen (dPD 0.37 +/- 0.07 vs. ndPD 0.28 +/- 0.13, p = 0.03) than in ndPD patients. Our results suggest that in vivo DAT density is increased in dPD patients as compared to ndPD, suggesting that DAT is implicated in the pathophysiology of PD depression.

Apathy may herald cognitive decline and dementia in Parkinson's disease

Apathy is usually defined as a lack of motivation. It may occur as part of another disorder (notably depression and dementia) or as an isolated syndrome. In Parkinson's disease (PD), apathy is common and several studies have reported an association between this condition and more severe cognitive symptoms, such as executive dysfunction. However, this association has not been thoroughly investigated. The aim of this study (in nondepressed, nondemented PD patients) was to examine whether or not cognitive decline and/or dementia occurred more frequently in apathetic subjects than in nonapathetic subjects. Forty consecutive PD patients participated in the study (20 with apathy and 20 without). None of the subjects were either demented or depressed at the time of study entry. The patients' cognitive functions were extensively assessed twice: at study entry and after an 18-month follow-up period. At study entry, the apathetic PD patients had significantly lower global cognitive status and executive function scores than the nonapathetic subjects. After a median period of 18 months, the rate of conversion to dementia was found to be significantly higher in the apathetic group than in the nonapathetic group (8 of 20 and 1 of 20, respectively). Even in nondemented patients, the decrease over time in cognitive performance (mainly executive function but also memory impairment) was significantly greater in apathetic subjects than in nonapathetic subjects. These findings suggest that in nondemented, nondepressed PD patients, apathy may be a predictive factor for dementia and cognitive decline over time.

Dopaminergic Modulation of Amygdala Activity During Emotion Recognition in Patients With Parkinson Disease

Variable findings have been reported for emotional processing in patients with Parkinson disease (PD). These contradictions could be due to differences in the progression of dopamine (DA) depletion. Levodopa treatment could have either beneficial or detrimental effects on brain functions modulated by DA according to disease progression. In healthy subjects, levodopa administration leads to a decreased amygdala activation in response to emotional tasks. Because it is known that there is a link between DA loss in mesolimbic system and depression, we hypothesized that PD patients without depression would have spared limbic DA projections. Consequently, levodopa medication could overdose limbic regions relative to severe dorsal striatal denervation. To evaluate the effect of levodopa on amygdala activation, we conducted a functional magnetic resonance imaging study in nondemented, nondepressed PD patients compared with healthy volunteers. Patients with PD and healthy subjects received either levodopa or placebo in 2 functional magnetic resonance imaging sessions. Amygdala activation was evaluated during a facial emotion recognition task. A similar right-amygdala activity was seen in both healthy subjects and PD patients in the placebo session. After levodopa administration, activity was reduced in both groups. In the patients, the levodopa dose used significantly improved motor dysfunction. Nondemented, nondepressed PD patients thus seem to have relatively preserved DA mesolimbic projections, and consequently, the same dose of levodopa needed to correct the lack of DA in the severely depleted putamen (motor part of striatum) would incidentally overdose the mesolimbic projections toward the amygdala.

The relation of testosterone levels with fatigue and apathy in Parkinson's disease

Objective Fatigue and apathy are frequent in patients with Parkinson's disease (PD). Testosterone deficiency in male patients may contribute in development of fatigue and apathy as well. We investigated whether a possible relation exists between serum testosterone levels, fatigue and apathy in male PD patients. Materials and methods We included 29 non-demented and non-depressed PD patients and 30 age- and sex-matched healthy subjects. Fatigue Severity Scale (FSS) and Apathy Evaluation Scale (AES-C) were used for the evaluations. In PD patients and healthy subjects, a relationship between FSS, AES-C scores and plasma testosterone levels were assessed. In addition, a correlation between FSS, AES-C and Unified Parkinson's Disease Rating Scale was investigated in PD group. Results The mean scores of FSS and AES-C were significantly higher in PD patients than those of the control group. The Unified Parkinson's Disease Rating Scale (UPDRS) scores were significantly correlated with FSS and AES-C scores. Mean free testosterone level was significantly lower in PD patients than controls ( p = 0.008). f-Testosterone levels of PD patients were not correlated with FSS or AES-C scores. Conclusion Apathy and fatigue are frequent in PD and show significant correlation with the severity of the disease. f-Testosterone levels are not related with apathy or fatigue in male PD patients and the role of testosterone in the pathophysiology of these non-motor symptoms is still controversial.

Monoamine transporter availability in Parkinson’s disease patients with or without depression

Depression is a common symptom in patients suffering from Parkinson's disease (PD) and markedly reduces their quality of life. As post-mortem studies have shown, its presence may reflect extensive cell loss in the midbrain and brainstem with imbalances in monoaminergic neurotransmitters. However, in vivo evidence of specific monoaminergic deficits in depressed PD patients is still sparse. Therefore, we studied PD patients with depression (PD+D) and without depression (PD-D) using high-resolution single-photon emission computed tomography (SPECT) and the monoamine transporter marker [(123)I]FP-CIT. A magnetic resonance imaging-based region-of-interest analysis was applied to quantify the specific-to-nondisplaceable [(123)I]FP-CIT binding coefficient V(3)'' in the striatum, thalamus and midbrain/brainstem regions. PD+D patients had significantly lower V(3)'' compared with PD-D patients in the striatum (p<0.001), thalamus (p=0.002), and midbrain/brainstem (p=0.025). Only PD+D patients without selective serotonin reuptake inhibitor (SSRI) treatment showed lower thalamic and midbrain V(3)'' than controls (p<0.001, p=0.029). In a small sub-group of SSRI-treated PD+D patients neither thalamic V(3)'' nor midbrain/brainstem V(3)'' differed from those in PD-D patients (p=0.168, p=0.201) or controls (p=0.384, p=0.318). Our data indicate that depression in PD is associated with a more pronounced loss of striatal dopamine transporter availability that is most likely secondary to increased dopaminergic degeneration. In addition, depressed PD patients have a lower availability of midbrain/brainstem monoamine transporters than nondepressed PD patients. These findings provide in vivo evidence in support of the known post-mortem data demonstrating more extensive nerve cell loss in PD with depression and indicate that SPECT imaging can help to identify pathophysiological changes underlying nonmotor symptoms in this common movement disorder.

The neuropathological basis for depression in Parkinson's disease

Depression is found in 30–40% of all patients with Parkinson's disease (PD), but its etiology is unclear. Using neuropathology as a signpost for neurotransmitter function, we investigated the prevalence of pathological features found at postmortem and sought to uncover differences between depressed ( n = 11) and non-depressed ( n = 9) elderly PD patients. The results indicate a higher prevalence of pathological features in depressed compared to non-depressed PD patients, particularly in catecholamine areas of the brain; the locus coeruleus (neuronal loss: odds ratio = 7.2, p = 08; gliosis: odds ratio = 18.0, p = 008); dorsal vagus nerve (gliosis: odds ratio = 7.63, p < 0.05), and substantia nigra pars compacta (gliosis: odds ratio = 2.85, ns). However, neuropathological differences were absent in the dorsal raphe nuclei, amygdala, and cortical regions. Our evidence suggests that depression in PD is related more to catecholaminergic than serotonergic system dysfunction.