Brain Advance Access originally published online on February 28, 2007
Brain 2007 130(7):1799-1807; doi:10.1093/brain/awm017
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Parkinson's disease-like midbrain sonography abnormalities are frequent in depressive disorders
Departments of 1Neurology and 2Psychiatry and Psychotherapy, University of Rostock, Rostock, Germany
Correspondence to: Dr Uwe Walter, Department of Neurology, University of Rostock, Gehlsheimer Strasse 20, D-18147 Rostock, Germany E-mail: uwe.walter{at}med.uni-rostock.de
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Substantia nigra (SN) hyperechogenicity is a characteristic transcranial sonography (TCS) finding in idiopathic Parkinson's disease. SN hyperechogenicity, found also in
10% of healthy adults, was related to a subclinical malfunction of the nigrostriatal dopaminergic system on PET studies and is, therefore, thought to represent a risk marker for Parkinson's disease. Epidemiological findings suggest an increased risk in subjects with depression. To find out whether frequency of SN hyperechogenicity is increased in depression, we performed TCS of brainstem and basal ganglia in 200 subjects: 55 controls without depression and without Parkinson's disease, 55 subjects with depression without Parkinson's disease (D+PD–), 45 Parkinson's disease patients without depression (D–PD+) and 45 Parkinson's disease patients with depression (D+PD+). Marked SN hyperechogenicity was found in 13% of controls, 40% of D+PD– (
2 test, P = 0.001), 69% of D–PD+ (vs D+PD–, P = 0.004) and 87% of D+PD+ patients (vs D–PD+, P = 0.04). Reduced echogenicity of brainstem raphe, thought to reflect alteration of the serotonergic system, was more frequent in depressed than in non-depressed subjects, irrespective of presence of Parkinson's disease, confirming earlier reports. The combined finding of marked SN hyperechogenicity and reduced raphe echogenicity in Parkinson's disease patients, however, was clearly associated with a history of depression prior to Parkinson's disease onset, whereas in D+PD– patients this combined TCS abnormality was related to motor asymmetry. In D+PD+ patients with depression prior to Parkinson's disease onset (n = 12), larger SN echogenic sizes correlated with younger age at Parkinson's disease onset (Spearman test, r = –0.607, P = 0.036). TCS findings of other basal ganglia did not differ between the groups studied. Data suggest that in subjects with depression nigrostriatal vulnerability is frequent, and that TCS might be useful to detect individuals at risk for developing Parkinson's disease.
Key Words: transcranial sonography; major depression; adjustment disorder with depressed mood; Parkinson's disease; substantia nigra
Abbreviations: SN, substantia nigra; TCS, transcranial sonography
Received September 28, 2006. Revised January 15, 2007. Accepted January 17, 2007.
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Introduction |
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Depression is a frequent comorbid condition in Parkinson's disease (Cummings, 1992
). In a review of all studies of depression in Parkinson's disease published from 1992 to 1998, comprising a total of 5911 Parkinson's disease patients, 31% of patients were, at any given time, depressed (Brooks and Doder, 2001). Several reports indicate that depression may precede the diagnosis of Parkinson's disease (Mayeux et al., 1981; Nilsson et al., 2001; Schuurman et al., 2002; Leentjens et al., 2003). In large register studies, each spanning 15–16 years, the risk for depressed patients for developing Parkinson's disease was 2.2–3.1-fold compared to non-depressed controls (Nilsson et al., 2001; Schuurman et al., 2002; Leentjens et al., 2003). These studies suggest that either depression is an early symptom of Parkinson's disease or that depression is associated with a risk factor for Parkinson's disease (Lieberman, 2006).
Transcranial sonography (TCS) has proved reliable and sensitive in detecting basal ganglia abnormalities, e.g. of substantia nigra (SN) in idiopathic Parkinson's disease and of lenticular nucleus in atypical parkinsonian syndromes (Becker et al., 1995a; Berg et al., 2001a; Walter et al., 2002, 2003, 2004a). In more than 90% of Parkinson's disease patients, TCS reveals characteristic SN hyperechogenicity, which is stable during the course of the disease and is thought to reflect increased amounts of iron, bound to proteins other than ferritin, but not the progressive neurodegeneration in the SN (Berg et al., 2001a, 2002, 2005; Walter et al., 2002, 2003; Spiegel et al., 2006). Marked SN hyperechogenicity is also found in 10% of healthy adults aged between 20 and 80 years, and has been related to a functional impairment of the nigrostriatal dopaminergic system (Berg et al., 1999a, 2001b; Walter et al., 2004b). Therefore, SN hyperechogenicity has been proposed to indicate an increased risk for developing Parkinson's disease (Berg et al., 1999a, 2002) or a subclinical stage of the disease (Walter et al., 2004b).
To further test the hypothesis that depression is associated with an increased risk for Parkinson's disease, we studied the frequency of SN hyperechogenicity in patients with depression. For this, patients with depressive states without and with concomitant Parkinson's disease were compared with normal controls and with Parkinson's disease patients without depression.
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Patients
Altogether 200 subjects were studied: 55 non-parkinsonian patients with depressive disorder (D+PD–), 55 age-matched controls without any psychiatric or neurodegenerative disorder (D–PD–), 45 Parkinson's disease patients with concomitant depression (D+PD+) and 45 Parkinson's disease patients without depression (D–PD+). Table 1 shows their demographic data.
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Fifty-five D+PD– patients treated at the Department of Psychiatry and Psychotherapy of the University of Rostock were eligible for inclusion. Inclusion criteria were (i) present inpatient treatment of current depressive symptoms, (ii) the unequivocal classification of a depressive state according to DSM-IV diagnostic categories as specified later (American Psychiatric Association, 1994
) and (iii) transcranial insonability. Exclusion criteria were (i) symptomatic psychic disorders, (ii) depression with psychotic symptoms, (iii) other psychotic or schizophrenic disorders, (iv) recent neuroleptic treatment or (v) recent concomitant neurological disorders. Informed consent was obtained from each patient. Following the Structured Clinical Interview for DSM-IV Axis-I Disorders (First et al., 1996), 40 patients met the diagnostic criteria for major depressive disorder (MDD) and 15 for adjustment disorder with depressed mood (ADDM). The mean age of patients with MDD was 57.1 ± 12.7 years, and with ADDM 49.2 ± 11.3 years (t-test, P = 0.034). All patients were on antidepressant medication. At the time of TCS, MDD (ADDM) patients had a severity of depression of 21.4 ± 12.7 (20.6 ± 7.5; P = 0.77) on the Beck Depression Inventory (Beck et al., 1961), and of 19.5 ± 6.9 (21.6 ± 5.8; P = 0.32) on the Hamilton 21-item Depression Rating Scale (Hamilton, 1967). Severity of motor retardation on the motor part of the Unified Parkinson's disease Rating Scale (UPDRS-III) was 5.7 ± 4.6 in MDD, and 3.1 ± 2.8 in ADDM patients (P = 0.019) (Fahn et al., 1987). Motor asymmetry, defined as a right-to-left difference of side-specific scores of the UPDRS-III, was found in 21 D+PD– patients (17 with MDD, 4 with ADDM) none of whom fulfilled the diagnostic criteria of Parkinson's disease (Hughes et al., 1992). D+PD– patients without and with motor asymmetry did not differ with respect to gender (2 test, P > 0.4), age (t-test, P > 0.4), duration (P > 0.6), severity (P > 0.5) or diagnostic category of depression (2 test, P > 0.2).
All Parkinson's disease patients were treated in the movement disorder clinic at the Department of Neurology of the University of Rostock and fulfilled the British Brain Bank criteria for definite Parkinson's disease (Hughes et al., 1992). Their mean age was 66.1 ± 9.7, age at Parkinson's disease onset 58.4 ± 10.7 and Parkinson's disease duration 7.7 ± 6.4 years. At the time of TCS investigation, all patients were on sufficient antiparkinsonian medication and had a disease severity of 35.7 ± 19.7 on the UPDRS-III. All patients in group D+PD+ had a documented depressive syndrome fulfilling diagnostic criteria of MDD within the past 6 months and were on antidepressant medication. Twelve (27%) D+PD+ patients had a history of MDD prior to onset of Parkinson's disease, with a mean onset age of MDD of 48.0 ± 12.2 (range, 24–73) years and a mean latency between MDD and onset of Parkinson's disease of 7.5 ± 8.0 (range, 0.5–29) years. None of the D–PD+ patients had any history of MDD. Since SN echogenicity has been demonstrated to vary with age at onset and motor subtype of Parkinson's disease (Walter et al., 2007), patients in groups D–PD+ and D+PD+ were matched not only by age and gender but also by age of Parkinson's disease onset and Parkinson's disease motor subtype (Table 1).
As controls (group D–PD–) served healthy subjects (n = 18), patients with cardiogenic or vasogenic cerebral embolism in whom leucencephalopathy was excluded (n = 24), cardiogenic syncope (n = 4), transient global amnesia (n = 2), otogenic vertigo (n = 2), epilepsy (n = 1), meningioma (n = 1) or diseases of the peripheral nervous system (n = 3).
Transcranial brain sonography
TCS was performed through the preauricular acoustic bone windows using a colour-coded phased-array ultrasound system equipped with a 2.5-MHz transducer (Sonoline; Siemens, Erlangen, Germany). The ultrasound parameters chosen were: penetration depth 16 cm, dynamic range 50 dB, high persistence, reject 7. SN echogenic size measurements were performed on axial TCS scans automatically after manually encircling the outer circumference of SN's echogenic area. SN echogenic sizes of <0.2 cm2 are classified as normal, sizes of 0.25 cm2 and above as markedly hyperechogenic, and sizes in-between as moderately hyperechogenic (Berg et al., 1999a, 2001a; Walter et al., 2002). For classification of patients with respect to their SN echogenicity the greater value of bilateral SN echogenic sizes was used. For intergroup comparisons, both SN echogenic sizes of each individual were used. Echogenicity of the brainstem raphe was rated as reduced when its structure was interrupted or not visible, i.e. isoechogenic compared with the adjacent brain parenchyma (Becker et al., 1997; Berg et al., 1999b). Additionally, echogenicity of thalami, lenticular nuclei and heads of caudate nuclei was investigated and classified as hyperechogenic when it was more intense than the surrounding white matter (Walter et al., 2002, 2003, 2004a). Classification of patients with respect to echogenicity of lenticular nucleus, caudate nucleus and thalamus was based on the most affected side of the investigated brain structure. Widths of third ventricle and of frontal horns of lateral ventricles were measured on a standardized diencephalic axial scanning plane. All TCS examinations were performed by one experienced sonographer (U.W.) who was blinded to the clinical data of the patients. The individuals of groups D+PD– and D–PD– underwent a second TCS examination on the same day, performed by an independent sonographer (L.M., S.H.). TCS images of brain structures of all Parkinson's disease patients were stored and off-line analysed by a second investigator blind to clinical data. A structure was only regarded as abnormal on TCS, if the findings of both investigators agreed.
Statistics
Descriptive statistics are given as median with lower (25th percentile) and upper (75th percentile) quartile. Since SN echogenic sizes were not normally distributed, as demonstrated by the Shapiro–Wilks test, for group comparison of SN echogenic sizes the Mann–Whitney U test was used. Categorial data were analysed by 2 test. Comparison of means was performed with the t-test for independent samples. For comparison of echogenic sizes and of ventricle widths with age, age at disease onset, disease duration and clinical scores the Spearman correlation test was used. Interrater reliability was assessed by the Spearman correlation test (SN echogenic sizes) and by Cohen's kappa (Brainstem raphe echogenicity scores).
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TCS findings of SN, brainstem raphe, lenticular nucleus and caudate nucleus in the different groups studied are summarized in Table 2. SN and brainstem raphe were evaluated in all patients, whereas in five D+PD– patients, five D–PD+ patients and three D+PD+ patients lenticular and caudate nuclei were not assessable due to insufficient temporal acoustic bone windows.
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Substantia nigra echogenicity
Typical sonographic images of normal and hyperechogenic SN are shown in Fig. 1. Figure 2 shows the frequency of SN hyperechogenicity in groups D–PD–, D+PD–, D–PD+ and D+PD+. Sonographic measurements of SN echogenic sizes (performed by a second sonographer in groups D–PD– and D+PD–) proved adequately reproducible considering the smallness of structure measured (Spearman correlation, r = 0.77, P < 0.001). The median SN echogenic size (including bilateral measurements) of the controls (group D–PD–) was 0.14 (0.11; 0.18) cm2, and of depressive patients without Parkinson's disease (D+PD–) was 0.20 (0.15; 0.26) cm2 (Mann–Whitney U test, P < 0.001). In group D+PD–, no difference of SN echogenic sizes was found between patients with MDD and those with ADDM (P = 0.37). The median SN echogenic size in D–PD+ patients was 0.25 (0.22; 0.32) cm2 (compared with group D–PD–: P < 0.001; D+PD–: P < 0.001) and in D+PD+ patients 0.27 (0.24; 0.31) cm2 (compared with group D–PD–: P < 0.001; D+PD–: P < 0.001; D–PD+: P = 0.10). The frequency of patients with marked SN hyperechogenicity increased significantly in group D+PD– (40%) compared with group D–PD– (13%;
2 test, P = 0.001), in group D–PD+ (69%) compared with group D+PD– (P = 0.004) and in group D+PD+ (87%) compared with group D–PD+ (P = 0.04) (Fig. 2). Within group D+PD–, marked SN hyperechogenicity was found with same frequency in patients with MDD and with ADDM (each, 40%). Frequency of moderate SN hyperechogenicity did not differ between groups (each comparison, P > 0.1). Larger SN echogenic size of each individual did not correlate with severity of depression as measured on the BDI, either in group D+PD– or in group D+PD+ (Spearman test, each, P > 0.2). Also, there was no correlation of larger SN echogenic size with severity of motor symptoms as measured on the UPDRS-III in either group (each, P > 0.2). UPDRS-III scores in D+PD– patients with marked SN hyperechogenicity (5.8 ± 4.3) did not differ from scores in D+PD– patients without marked SN hyperechogenicity (4.4 ± 4.3; t-test, P = 0.24). No correlation was found between SN echogenic size and Parkinson's disease duration in groups D–PD+ and D+PD+. However, in group D+PD+, larger SN echogenic size correlated significantly with younger age at onset of Parkinson's disease (Spearman test, r = –0.364, P = 0.014), whereas no such correlation was found in group D–PD+ (P > 0.4). This correlation was stronger if only D+PD+ patients with onset of depression prior to onset of Parkinson's disease were analysed (r = –0.607, P = 0.036) (Fig. 3).
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Brainstem raphe echogenicity
The interrater reliability of brainstem raphe TCS (performed by a second sonographer in groups D–PD– and D+PD–) was high (Cohen's kappa 0.88, P < 0.001). The frequency of patients with reduced echogenicity of brainstem raphe was higher in group D+PD– compared with group D–PD–, and in group D+PD+ compared with group D–PD+ (Table 2, Fig. 4), but did not differ between groups D–PD– and D–PD+ (
2 test, P = 0.32) nor between groups D+PD– and D+PD+ (P = 0.14). Within group D+PD–, reduced echogenicity of brainstem raphe was found with same frequency in patients with MDD (52%) and with ADDM (53%). Patients with normal and reduced echogenicity of brainstem raphe did not differ with respect to severity of depression as measured on the BDI, neither in group D+PD– nor in group D+PD+ (t-test, each, P > 0.2). Also, there was no correlation between brainstem raphe echogenicity and UPDRS-III scores in either group (each, P > 0.2). No correlation was found between brainstem raphe echogenicity and age, age at Parkinson's disease onset or Parkinson's disease duration in groups D–PD+ and D+PD+. D+PD+ patients with onset of depression prior to onset of Parkinson's disease, however, exhibited reduced echogenicity of brainstem raphe in combination with marked SN hyperechogenicity more frequently (58%) than D+PD+ patients with later onset of depression (21%; 2 test, P = 0.017) (Fig. 5), whereas frequency of marked SN hyperechogenicity did not differ (P = 0.55). The combination of reduced echogenicity of brainstem raphe and marked SN hyperechogenicity was even less frequent in D–PD+ patients (13%, P = 0.001) and was not found in group D–PD–. Out of group D+PD–, patients with a combination of reduced brainstem raphe echogenicity and marked SN hyperechogenicity (n = 11) had more frequently a difference of UPDRS scores between the right and left side (73%) than patients without combination of these TCS abnormalities (39%; P = 0.046) (Fig. 5), whereas abnormal TCS of brainstem raphe or SN alone was not associated with asymmetric UPDRS scores. D+PD– patients with and without combination of these TCS abnormalities, however, did not differ with respect to gender (2 test, P = 0.9), age (t-test, P = 0.3), duration (P = 0.6), severity (P = 0.6) or diagnostic category of depression (2 test, P = 0.4). Combination of normal raphe echogenicity and marked SN hyperechogenicity was more frequent in Parkinson's disease patients (D–PD+, D+PD+, each group, 56%) than in groups D–PD– (13%, P < 0.001) and group D–PD– (20%, P < 0.001) but did not differ between groups D–PD– and D+PD– (P = 0.30).
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Other TCS findings
Caudate nucleus hyperechogenicity was more frequent in group D–PD+ compared with group D–PD– but the difference failed statistical significance (
2 test, P = 0.065). No differences were found if other groups were compared. Lenticular nucleus hyperechogenicity was detected with similar frequency in all groups studied. There was no correlation between clinical scores (BDI, UPDRS-III) and echogenicity of caudate or lenticular nucleus. Mean width of third ventricle did not differ between patients of group D–PD– (5.3 ± 3.1 mm) and those of group D+PD– (4.6 ± 2.1 mm, t-test, P = 0.13) nor between patients of group D–PD+ (7.4 ± 2.5 mm) and those of group D+PD+ (6.7 ± 2.5 mm, P = 0.20), but was larger in Parkinson's disease patients compared to non-parkinsonian subjects (P < 0.001). Mean width of frontal horns did not differ between patients of group D–PD– (14.1 ± 3.5 mm) and those of group D+PD– (13.3 ± 2.3 mm, P = 0.19) nor between patients of group D–PD+ (16.2 ± 3.6 mm) and those of group D+PD+ (14.9 ± 2.9 mm, P = 0.08), but was larger in Parkinson's disease patients compared to non-parkinsonian subjects (P < 0.01).
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Discussion |
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TCS data obtained in this study show that the finding of SN hyperechogenicity, which is characteristic for idiopathic Parkinson's disease, is also frequent in patients with depressive disorders. In non-parkinsonian subjects with depression, marked SN hyperechogenicity is found with a 3-fold frequency compared to the age-matched normal population. Reduced echogenicity of brainstem raphe is more frequent in depressed than in non-depressed patients, irrespective of presence of Parkinson's disease. The combination of marked SN hyperechogenicity and reduced raphe echogenicity, however, is significantly associated with a history of depressive disorder prior to onset of Parkinson's disease in Parkinson's disease patients, and with motor asymmetry in non-parkinsonian subjects with depression. In Parkinson's disease patients with depression prior to onset of Parkinson's disease, larger SN echogenic sizes were clearly correlated with earlier onset of Parkinson's disease. TCS abnormalities of caudate and lenticular nucleus were found with similar low frequency in all groups studied.
The found frequency of marked SN hyperechogenicity in Parkinson's disease patients and normal controls is in line with earlier reports (Berg et al., 2001a; Walter et al., 2002, 2003, 2007). This TCS feature is highly characteristic for idiopathic Parkinson's disease and correlates with younger age at Parkinson's disease onset, but does not change in the course of the disease (Berg et al., 2001a, 2005; Walter et al., 2007). Moreover, SN echogenicity in Parkinson's disease patients does not correlate with the degeneration of nigrostriatal dopaminergic neurons as measured with SPECT (Spiegel et al., 2006). SN hyperechogenicity in Parkinson's disease must therefore be regarded as a trait marker featuring the predisposition for the disease rather than a severity marker reflecting changes in SN architecture due to proceeding cell loss or continuous accumulation of toxic substances according to disease progression over time. Only 1–2% of subjects older than 60 years eventually develop Parkinson's disease, but neuropathological findings suggest that 10% of subjects older than 60 years reach presymptomatic stages of Parkinson's disease, exhibiting Lewy bodies and signs of neurodegeneration in the SN (Fearnley and Lees, 1991). This agrees with the frequency of marked SN hyperechogenicity in the normal population. Whereas the rate of individuals with SN hyperechogenicity does not change with age in adults (Berg et al., 1999a), elderly patients without prediagnosed extrapyramidal disorder but with SN hyperechogenicity develop more frequent and more severe signs of motor retardation and in some cases even typical Parkinson's disease than those with a regular echogenicity of the SN (Berg et al., 2001c). Moreover, patients with SN hyperechogenicity but without prediagnosed Parkinson's disease developed more often and more severe extrapyramidal symptoms when neuroleptic therapy had to be applied (Berg et al., 2001b). These clinical observations substantiate the functional relevance of SN hyperechogenicity in healthy adults. In several PET and SPECT studies of young healthy subjects, marked SN hyperechogenicity has been associated to a subclinical impairment of the nigrostriatal dopaminergic system (Berg et al., 1999a, 2002; Sommer et al., 2004; Walter et al., 2004b).
In the present study a 3-fold rate of marked SN hyperechogenicity was found in depressed non-parkinsonian patients compared to the normal population. This is in line with the results of epidemiological studies that have estimated a risk of 2.2 to 3.1 for depressed patients for later developing Parkinson's disease compared to non-depressed controls (Nilsson et al., 2001; Schuurman et al., 2002; Leentjens et al., 2003). Few studies of the nigrostriatal dopaminergic system in depressed patients without Parkinson's disease have been reported. Abnormal speech articulation patterns in depressed patients similar to that of Parkinson's disease patients (Flint et al., 1993), increased frequency of motor retardation in patients with major depression (Lemke et al., 1999, 2000), and Parkinson's disease-like decrease of striatal dopamine transporter density in depressed patients on SPECT studies (Neumeister et al., 2001) suggest an impairment of the nigrostriatal dopaminergic system in depression. Findings of a recent functional MRI study in non-parkinsonian patients with major depression imply involvement of dopamine-related neuroanatomical substrates of the ventrolateral prefrontal cortex, the orbitofrontal cortex and the striatum in altered reward processing and anhedonic symptoms (Tremblay et al., 2005). The dopaminergic projections arise from neurons in the ventral mesencephalon near the SN and project to limbic and cortical structures that mediate reward processing and cognition. Whereas little is known on the degree of degeneration of mesencephalic dopaminergic neurons in non-parkinsonian depressed subjects, neuropathological studies in depressed Parkinson's disease patients have shown that there is a greater degeneration of dopaminergic neurons in the ventral mesencephalon than in non-depressed Parkinson's disease patients (Kapur and Mann, 1992). Findings of a recent PET study support the idea that depression in Parkinson's disease might be associated with a loss of dopamine (and noradrenaline) innervation in the limbic system (Remy et al., 2005). The higher frequency of marked SN hyperechogenicity in depressed compared to non-depressed Parkinson's disease patients, found in the present study, might be a correlate of a more widespread pathology involving mesolimbic dopaminergic neurons in Parkinson's disease patients with depression, even though it has to be considered that SN hyperechogenicity does not reflect the neuronal degeneration itself (Spiegel et al., 2006). Since the pathology underlying SN hyperechogenicity is already present at early adult ages, this might also lead to a liability to depression via altered mesolimbic dopaminergic activity, prior to, or even independently from a possible manifestation of Parkinson's disease later in life. Findings of the present study suggest that TCS of SN might be useful to detect those patients with depressive disorder who are at increased risk of developing Parkinson's disease. To further substantiate the proposed association of depression and the development of Parkinson's disease, functional neuroimaging studies in patients with depression and SN hyperechogenicity but without the clinical picture of Parkinson's disease are warranted.
Brainstem raphe TCS findings agree with previous reports of reduced echogenicity of brainstem raphe as a characteristic finding in MDD and in depression associated with Parkinson's disease, but rarely in healthy adults, bipolar affective disorders, schizophrenia or Parkinson's disease without depression (Becker et al., 1995b, 1997; Berg et al., 1999b; Walter et al., 2007). This TCS finding could be correlated to signal alteration on MRI and was suggested to reflect structural disruption of the brainstem raphe, resulting in impaired serotonergic innervation (Berg et al., 1999b; Becker et al., 2001). In the present study, mean raphe echogenicity scores in depressed patients are higher compared to earlier reported scores which can be attributed to improvements in the ultrasound technology in recent years. Becker and co-workers (1995, 1997) applied an ultrasound system of former generation (Sonoline CF; Siemens, Erlangen, Germany), whereas the ultrasound system used in this study was a present-day machine displaying brain structures with higher sensitivity which made classification of brainstem raphe echogenicity as markedly reduced (i.e. invisible) or moderately reduced (i.e. interrupted) less likely. A similar effect has been previously demonstrated for measurement of SN echogenicity with the respective ultrasound systems (Berg et al., 2001a). Nevertheless, high interrater correlation in this and earlier studies underlines reliability of brainstem raphe TCS.
To further elucidate whether TCS findings are helpful for detection of depressive patients with an increased risk for developing Parkinson's disease, we compared TCS findings in Parkinson's disease patients who had depressive disorder prior to Parkinson's disease onset, and those without or with later onset of depression. It turned out that the combination of the findings of marked SN hyperechogenicity and reduced raphe echogenicity is characteristic for Parkinson's disease patients with depressive disorder prior to onset of Parkinson's disease, and that, in non-parkinsonian patients with depression, these combined TCS abnormalities are significantly associated with presence of right-to-left asymmetry on the UPDRS. Neither severity, duration or diagnostic category of depression, nor gender or age were found to have an impact on the TCS abnormalities or on the presence of motor asymmetry in non-parkinsonian patients with depression in this study. It is well-known that mild, subclinical motor asymmetry may occur 10–20 years before the diagnosis of Parkinson's disease can be established according to diagnostic criteria (Lees, 1992). Also, depressive and anxiety disorders may occur already 10–20 years before onset of Parkinson's disease (Shiba et al., 2000). As psychomotor retardation is frequent in depressive disorders (Lemke et al., 1999, 2000), a prevalent liability to motor asymmetry might emerge with the depressive state. The underlying mechanism, possibly indicated by sonographic abnormality of brainstem raphe, might be an impaired serotonin-mediated regulation of striatal dopamine transmission (Alex et al., 2005). Interestingly, in Parkinson's disease patients with onset of depression prior to onset of Parkinson's disease, a clear correlation of larger SN echogenic sizes with earlier onset of Parkinson's disease was seen in the present study. A similar high correlation was demonstrated previously in parkin mutation carriers who were members of the same kindred (Walter et al., 2004b). It needs to be elucidated in further studies whether, or not, this similarity is due to a predominantly genetic determination of Parkinson's disease in subjects who suffer depression prior to onset of Parkinson's disease as proposed earlier (Santamaria et al., 1986). Findings of the present study suggest that depressed patients with combined TCS abnormality of SN and brainstem raphe are at increased risk of developing Parkinson's disease. This needs to be confirmed in long-term follow-up studies of these patients.
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References |
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Alex KD, Yavanian GJ, McFarlane HG, Pluto CP, Pehek EA. Modulation of dopamine release by striatal 5-HT2C receptors. Synapse (2005) 55:242–51.[CrossRef][Web of Science][Medline]
American Psychiatric Association. Diagnostic and statistical manual of mental disorders (1994) 4th edn. Washington, DC: American Psychiatric Association.
Beck AT, Ward CH, Mendelson M, Mock J, Erbaugh J. An inventory for measuring depression. Arch Gen Psychiatry (1961) 4:561–71.
Becker G, Seufert J, Bogdahn U, Reichmann H, Reiners K. Degeneration of substantia nigra in chronic Parkinson's disease visualized by transcranial color-coded real-time sonography. Neurology (1995a) 45:182–4.
Becker G, Becker T, Struck M, Lindner A, Burzer K, Retz W, et al. Reduced echogenicity of brainstem raphe specific to unipolar depression: a transcranial color-coded real-time sonography study. Biol Psychiatry (1995b) 38:180–4.[CrossRef][Web of Science][Medline]
Becker T, Becker G, Seufert J, Hofmann E, Lange KW, Naumann M, et al. Parkinson's disease and depression: evidence for an alteration of the basal limbic system detected by transcranial sonography. J Neurol Neurosurg Psychiatry (1997) 63:590–6.
Becker G, Berg D, Lesch KP, Becker T. Basal limbic system alteration in major depression: a hypothesis supported by transcranial sonography and MRI findings. Int J Neuropsychopharmacol (2001) 4:21–31.[CrossRef][Web of Science][Medline]
Berg D, Becker G, Zeiler B, Tucha O, Hofmann E, Preier M, et al. Vulnerability of the nigrostriatal system as detected by transcranial ultrasound. Neurology (1999a) 53:1026–31.
Berg D, Supprian T, Hofmann E, Zeiler B, Jager A, Lange KW, et al. Depression in Parkinson's disease: brainstem midline alteration on transcranial sonography and magnetic resonance imaging. J Neurol (1999b) 246:1186–93.[CrossRef][Web of Science][Medline]
Berg D, Siefker C, Becker G. Echogenicity of the substantia nigra in Parkinson's disease and its relation to clinical findings. J Neurol (2001a) 248:684–9.[CrossRef][Web of Science][Medline]
Berg D, Jabs B, Merschdorf U, Beckmann H, Becker G. Echogenicity of substantia nigra determined by transcranial ultrasound correlates with severity of parkinsonian symptoms induced by neuroleptic therapy. Biol Psychiatry (2001b) 50:463–7.[CrossRef][Web of Science][Medline]
Berg D, Siefker C, Ruprecht-Dorfler P, Becker G. Relationship of substantia nigra echogenicity and motor function in elderly subjects. Neurology (2001c) 56:13–7.
Berg D, Roggendorf W, Schroder U, Klein R, Tatschner T, Benz P, et al. Echogenicity of the substantia nigra: association with increased iron content and marker for susceptibility to nigrostriatal injury. Arch Neurol (2002) 56:999–1005.
Berg D, Merz B, Reiners K, Naumann M, Becker G. Five-year follow-up study of hyperechogenicity of the substantia nigra in Parkinson's disease. Mov Disord (2005) 20:383–5.[CrossRef][Web of Science][Medline]
Brooks DJ, Doder M. Depression in Parkinson's disease. Curr Opin Neurol (2001) 14:465–70.[CrossRef][Web of Science][Medline]
Cummings JL. Depression and Parkinson's disease: a review. Am J Psychiatry (1992) 149:443–54.
Fahn S, Elton RL, Members of the UPDRS Development Committee. Unified Parkinson's Disease Rating Scale. In: Recent developments in Parkinson's disease II—Fahn S, Marsden CD, Goldstein M, et al, eds. (1987) 1st edn. New York: Macmillan. 153–63.
Fearnley JM, Lees AJ. Ageing and Parkinson's disease: substantia nigra regional selectivity. Brain (1991) 114:2283–301.
First MB, Spitzer RL, Gibbon M, Williams JBW. Structured clinical interview for DSM-IV axis I disorders, clinician version (SCID-CV) (1996) Washington, DC: American Psychiatric Press.
Flint AJ, Black SE, Campbell-Taylor I, Gailey GF, Levinton C. Abnormal speech articulation, psychomotor retardation, and subcortical dysfunction in major depression. J Psychiatr Res (1993) 27:309–19.[CrossRef][Web of Science][Medline]
Hamilton M. Development of a rating scale for primary depressive illness. Br J Soc Clin Psychol (1967) 6:278–96.[Medline]
Hughes AJ, Daniel SE, Kilford L, Lees AJ. Accuracy of clinical diagnosis of idiopathic Parkinson's disease: a clinico-pathological study of 100 cases. J Neurol Neurosurg Psychiatry (1992) 55:181–4.
Kapur S, Mann JJ. Role of the dopaminergic system in depression. Biol Psychiatry (1992) 32:1–17.[CrossRef][Web of Science][Medline]
Lees AJ. When did Ray Kennedy's Parkinson's disease begin? Mov Disord (1992) 7:110–6.[Web of Science][Medline]
Leentjens AF, Van den Akker M, Metsemakers JF, Lousberg R, Verhey FR. Higher incidence of depression preceding the onset of Parkinson's disease: a register study. Mov Disord (2003) 18:414–8.[CrossRef][Web of Science][Medline]
Lemke MR, Koethe NH, Schleidt M. Timing of movements in depressed patients and healthy controls. J Affect Disord (1999) 56:209–14.[CrossRef][Web of Science][Medline]
Lemke MR, Wendorff T, Mieth B, Buhl K, Linnemann M. Spatiotemporal gait patterns during over ground locomotion in major depression compared with healthy controls. J Psychiatr Res (2000) 34:277–83.[CrossRef][Web of Science][Medline]
Lieberman A. Depression in Parkinson's disease – a review. Acta Neurol Scand (2006) 113:1–8.[Web of Science][Medline]
Mayeux R, Stern Y, Rosen J, Leventhal J. Depression, intellectual impairment, and Parkinson disease. Neurology (1981) 31:645–50.
Neumeister A, Willeit M, Praschak-Rieder N, Asenbaum S, Stastny J, Hilger E, Pirker W, Konstantinidis A, Kasper S. Dopamine transporter availability in symptomatic depressed patients with seasonal affective disorder and healthy controls. Psychol Med (2001) 31:1467–73.[Web of Science][Medline]
Nilsson FM, Kessing LV, Bolwig TG. Increased risk of developing Parkinson's disease for patients with major affective disorder: a register study. Acta Psychiatr Scand (2001) 104:380–6.[CrossRef][Web of Science][Medline]
Remy P, Doder M, Lees A, Turjanski N, Brooks D. Depression in Parkinson's disease: loss of dopamine and noradrenaline innervation in the limbic system. Brain (2005) 128:1314–22.
Santamaria J, Tolosa E, Valles A. Parkinson's disease with depression: a possible subgroup of idiopathic parkinsonism. Neurology (1986) 36:1130–3.
Schuurman AG, van den Akker M, Ensinck KT, Metsemakers JF, Knottnerus JA, Leentjens AF, et al. Increased risk of Parkinson's disease after depression: a retrospective cohort study. Neurology (2002) 58:1501–4.
Shiba M, Bower JH, Maraganore DM, McDonnell SK, Peterson BJ, Ahlskog JE, et al. Anxiety disorders and depressive disorders preceding Parkinson's disease: a case-control study. Mov Disord (2000) 15:669–77.[CrossRef][Web of Science][Medline]
Sommer U, Hummel T, Cormann K, Mueller A, Frasnelli J, Kropp J, et al. Detection of presymptomatic Parkinson's disease: combining smell tests, transcranial sonography, and SPECT. Mov Disord (2004) 19:1196–202.[CrossRef][Web of Science][Medline]
Spiegel J, Hellwig D, Mollers MO, Behnke S, Jost W, Fassbender K, et al. Transcranial sonography and [123I]FP-CIT SPECT disclose complementary aspects of Parkinson's disease. Brain (2006) 129:1188–93.
Tremblay LK, Naranjo CA, Graham SJ, Hermann N, Mayberg HS, Hevenor S, et al. Functional neuroanatomical substrates of altered reward processing in major depressive disorder revealed by a dopaminergic probe. Arch Gen Psychiatry (2005) 62:1228–36.
Walter U, Wittstock M, Benecke R, Dressler D. Substantia nigra echogenicity is normal in non-extrapyramidal cerebral disorders but increased in Parkinson's disease. J Neural Transm (2002) 109:191–6.[CrossRef][Web of Science][Medline]
Walter U, Niehaus L, Probst T, Benecke R, Meyer BU, Dressler D. Brain parenchyma sonography discriminates Parkinson's disease and atypical parkinsonian syndromes. Neurology (2003) 60:74–7.
Walter U, Dressler D, Wolters A, Probst T, Grossmann A, Benecke R. Sonographic discrimination of corticobasal degeneration vs progressive supranuclear palsy. Neurology (2004a) 63:504–9.
Walter U, Klein C, Hilker R, Benecke R, Pramstaller PP, Dressler D. Brain parenchyma sonography detects preclinical parkinsonism. Mov Disord (2004b) 19:1445–9.[CrossRef][Web of Science][Medline]
Walter U, Dressler D, Wolters A, Wittstock M, Benecke R. Transcranial brain sonography findings in clinical subgroups of idiopathic Parkinson's disease. Mov Disord (2007) 22:48–54.[CrossRef][Medline]
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