Journal of Neurology

, Volume 258, Issue 12, pp 2248–2253

Subclinical nigrostriatal dopaminergic denervation in the cerebellar subtype of multiple system atrophy (MSA-C)

Authors

    • Parkinson’s Disease and Movement Disorders Unit, Neurology Service, Institut Clínic de Neurociències (ICN), Hospital Clínic i UniversitariInstitut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Centro de Investigación en Red de Enfermedades Neurodegenerativas (CIBERNED)
  • Alex Iranzo
    • Sleep Disorders Unit, Neurology Service, ICN, Hospital Clínic i UniversitariIDIBAPS, CIBERNED
  • Sebastian Rauek
    • Parkinson’s Disease and Movement Disorders Unit, Neurology Service, Institut Clínic de Neurociències (ICN), Hospital Clínic i UniversitariInstitut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Centro de Investigación en Red de Enfermedades Neurodegenerativas (CIBERNED)
  • Francisco Lomeña
    • Nuclear Medicine Service, Centre de Diagnòstic per la Imatge (CDI), Hospital Clínic i UniversitariInstitut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS)
  • Judith Gallego
    • Biophysics Unit, Department of Physiological Sciences IBiomedical Research Networking Centre in Bioengineering, Biomaterials and Nanomedicine (CIBERBBN), University of Barcelona
  • Doménec Ros
    • Biophysics Unit, Department of Physiological Sciences IBiomedical Research Networking Centre in Bioengineering, Biomaterials and Nanomedicine (CIBERBBN), University of Barcelona
  • Joan Santamaría
    • Sleep Disorders Unit, Neurology Service, ICN, Hospital Clínic i UniversitariIDIBAPS, CIBERNED
  • Eduardo Tolosa
    • Parkinson’s Disease and Movement Disorders Unit, Neurology Service, Institut Clínic de Neurociències (ICN), Hospital Clínic i UniversitariInstitut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Centro de Investigación en Red de Enfermedades Neurodegenerativas (CIBERNED)
Original Communication

DOI: 10.1007/s00415-011-6108-8

Cite this article as:
Muñoz, E., Iranzo, A., Rauek, S. et al. J Neurol (2011) 258: 2248. doi:10.1007/s00415-011-6108-8

Abstract

Nigrostriatal involvement is considered an additional feature in the new consensus criteria for the diagnosis of the cerebellar variant of multiple system atrophy (MSA-C). However, so far, only a few studies, which include a relative small number of patients, give support to this criterion. Our objective was to assess nigrostriatal dopaminergic innervation in patients with MSA-C without parkinsonism by use of dopamine transporter single photon emission computed tomography (DAT SPECT). Thirteen patients that fulfilled criteria for possible or probable MSA-C and presented no parkinsonian signs, and 12 age-matched healthy controls underwent (123I-2-β-carbomethoxy-3β-(4-iodophenyl)-N-(3-fluoropropyl) nortropane ([123I]FP-CIT) SPECT. Patients were also evaluated through the Unified Multiple System Atrophy Rating Scale (UMSARS) and brain magnetic resonance imaging (MRI). The mean duration of the cerebellar syndrome was 3.8 ± 1.7 years. DAT SPECT showed a significant decrease of striatal [123I]FP-CIT uptake ratios in patients (p < 0.001). Radiotracer uptake reduction was 21% in the entire striatum, 19% in putamen, and 24% in caudate nuclei. Striatal binding ratios were within the normal range in 3 patients. We did not find correlation between striatal uptake and disease duration, age of patients, UMSARS-II score, and pontine diameter. [123I]FP-CIT SPECT shows that most but not all MSA-C patients without parkinsonism have subclinical nigrostriatal dopaminergic denervation which is not related to disease duration, cerebellar dysfunction, or pontine atrophy.

Keywords

Multiple system atrophyMSA-CDopamine transporterSPECTNigrostriatal dopaminergic denervation

Introduction

Multiple system atrophy (MSA) is an adult-onset sporadic disease characterised by parkinsonism, cerebellar ataxia, pyramidal signs, and autonomic dysfunction. The different predominance of symptoms gives rise to different subtypes. The parkinsonian subtype (MSA-P) is defined when bradykinesia with rigidity, tremor or postural instability dominate the clinical picture. The cerebellar form (MSA-C) is considered when cerebellar ataxia is the most prominent symptom. In Europe and North America, more than 60% of the MSA cases correspond to the parkinsonian subtype [1, 2], whereas in Japan more than 80% of the cases present with the cerebellar form [3], thus, suggesting a role for the different genetic background or environmental factors in the development of MSA subtypes. The first consensus criteria on the diagnosis of MSA were published in 1999 [4], but they have been more recently revised in a second consensus statement. The new diagnostic criteria consider now abundant α-synuclein-positive glial cytoplasmic inclusions as neuropathological hallmarks and try to improve the recognition of patients with early or possible MSA by including red flags and neuroimaging aspects [5]. Currently, the diagnosis of possible MSA-C is considered in the presence of a cerebellar syndrome (gait ataxia with cerebellar dysarthria, limb ataxia, or cerebellar oculomotor dysfunction) and at least one feature suggesting autonomic dysfunction (otherwise unexplained urinary urgency, frequency or incomplete bladder emptying, erectile dysfunction in males, or significant orthostatic blood pressure decline that does not meet the level required in probable MSA). In addition, at least one of the additional features has to be present: pyramidal signs, stridor, parkinsonism, atrophy on magnetic resonance imaging (MRI) of putamen, middle cerebellar peduncle or pons, putaminal hypometabolism on [18F]fluorodeoxyglucose PET in putamen, or presynaptic nigrostriatal dopaminergic denervation on SPECT or PET studies.

However, only a few studies have demonstrated subclinical nigrostriatal involvement in MSA-C [6]. The aim of the present work was to investigate presynaptic nigrostriatal dopaminergic innervation in patients with established MSA-C without clinical parkinsonism through striatal dopamine transporter (DAT) SPECT with (123I-2-β-carbomethoxy-3β-(4-iodophenyl)-N-(3-fluoropropyl)nortropane ([123I]FP-CIT).

Methods

Subjects

Thirteen patients (9 men/4 women) fulfilling clinical criteria for possible or probable MSA-C [5] without parkinsonism, and 12 age-matched healthy control subjects (7 men/5 women) were recruited at the Movement Disorders clinics at the Hospital Clinic of Barcelona. Patients and controls had no family history of ataxia or parkinsonism. Genetic study for dominant inherited spinocerebellar ataxias SCA1, SCA2, SCA3, SCA6, SCA7, SCA8, and DRPLA, and for fragile X-associated tremor/ataxia syndrome (FXTAS), previously performed in five patients with disease onset before 55 years of age did not show any trinucleotide repeat expansion.

The diagnosis of probable MSA-C required the presence of a sporadic cerebellar syndrome associated with urinary incontinence or significant orthostatic hypotension with a decrease in blood pressure of at least 30 mm Hg systolic and 15 mm Hg diastolic within 3 min after standing up. Possible MSA-C was diagnosed when patients, in addition to the cerebellar syndrome, complained of erectile dysfunction or urinary urgency, but not incontinence, and had stridor or pontine and cerebellar atrophy on MRI. Patients were clinically evaluated through the Unified Multiple System Atrophy Rating Scale (UMSARS) [7]. None of the participants were taking centrally nervous system active medications known to influence strial radiotracer binding. Disease onset was considered to occur when patients reported to start with the cerebellar symptoms. Demographical and clinical data were recorded at the time of DAT SPECT was performed.

The study was approved by the Ethical Committee of the Hospital Clinic of Barcelona. Written informed consent was obtained from all participants.

Dopamine transporter SPECT

All participants underwent intravenous administration of 185 MBq of [123I]FP-CIT (DaTSCAN, GE Healthcare, Eindhoven, The Netherlands) after thyroid gland blockade with a Lugol’s solution. SPECT acquisition was performed 4 h post-injection, using a doubled head gamma camera (E-CAM, Dual head, Siemens Medical System, Erlangen, Germany) fitted with low energy high resolution collimators.

The parameters of acquisition were the following: rotation radius of 15 cm, circular orbit; zoom of 1.23; matrix size of 128 × 128, pixel size 3.9 mm; 128 projections, 40 s/projection; energy window 20% over 159 keV. A minimum of 2 million counts per every single acquisition was collected in all cases. Two-dimensional (2D) reconstruction using filtered back projections, with a Butterworth filter (10th order, 0.5) and attenuation correction (Chang’s method; μ = 0.11/cm) was done, and reconstructed transaxial slices were displayed for quantitative analysis. Prismatic volumes (area: 36 mm2, high 32 mm) of regions of interest (ROIs) were placed in the anterior and posterior putamen and the head of caudate nucleus. As a reference, we used the occipital cortex uptake on both hemispheres, drawing an irregular volume of interest (area 27.24 cm2, high 32 mm).

We calculated the striatal/occipital cortex specific binding ratios for the caudate, anterior and posterior putamen, entire putamen and entire striatum on each hemisphere and bilaterally. Entire putamen was the mean of the anterior and posterior putamen uptakes and entire striatum was the mean of the entire putamen uptake and caudate nucleus uptake. Bilateral striatal binding ratios were calculated as the mean between the left and the right side for the different ROIs. Striatal uptake was considered pathological when were below 2 standard deviations (SD) of the mean striatal uptake measured in the controls.

Magnetic resonance imaging

Conventional brain MRI at 1.5 T was performed in 11 patients. Two patients refused to undergo MRI study because of claustrophobic concerns. We searched for signal alterations in DP and T2-weigthed sequences in the putamen (“slit-like void signal”), pons (“hot cross bun” sign), and middle cerebellar peduncles. In addition, a semiquantitative analysis of the degree of atrophy of pons and cerebellum and a quantitative analysis measuring the anterior–posterior diameter of the pons at its largest distance perpendicular to the floor of the fourth ventricle were performed as previously described [8].

Statistical analysis

Statistical analysis was performed using SPSS 16.0 software (SPSS, Chicago, IL). Striatal binding ratios of MSA-C patients and controls were compared by means of the Mann–Whitney U test. Correlations between striatal uptake and age, disease duration, UMSARS, and pontine diameter were performed with the calculation of the Pearson correlation coefficient.

Results

The demographic, clinical, and MRI data of patients are shown in Table 1. Eight patients fulfilled criteria of possible and 5 of probable MSA-C. One with probable MSA-C presented urinary incontinence (patient 7) and the other four had significant orthostatic hypotension (patients 1, 3, 12, 13) that was symptomatic in 2 patients (patients 3 and 13). Laryngeal stridor was documented in 6 patients. All patients had REM behavior disorder (RBD) confirmed by polysomnography. In four of them, RBD preceded the cerebellar symptoms by several years. The interval between the onset of cerebellar and DAT SPECT imaging was 3.8 ± 1.7 years. UMSARS part I score was 21.3 ± 5.2, and part II was 14.8 ± 7.6. There was not a significant difference between the age of patients and controls (mean of patients: 61 ± 8; mean of controls: 64.6 ± 5.6; p = 0.2).
Table 1

Demographic, clinical, and MRI features of MSA-C patients

Patient

Gender

Age at onseta

Age at SPECT

Other symptoms

UMSARS- II score

MRI atrophy

Abnormal MRI signal

Pontine diameter (mm)

Cb

Pons

Pons

MCP

Putamen

1

M

52

55

Urinary urgency, orthostatic hypotension

6

++

++

+

20

2

M

52

57

Erectile dysfunction, stridor

21

++

+++

++

+

15

3

M

62

65

Erectile dysfunction, orthostatic hypotension, stridor

14

+

++

+

20

4

F

57

62

Urinary urgency

26

+++

++

++

++

19

5

F

61

63

Urinary urgency

7

++

++

++

+

18

6

M

66

68

Urinary urgency

8

++

++

+

19

7

F

41

48

Urinary incontinence

31

++

++

++

++

15

8

F

72

74

Urinary urgency

16

++

+++

++

+

16

9

M

50

52

Erectile dysfunction, stridor

9

ND

ND

ND

ND

ND

ND

10

M

61

67

Erectile dysfunction, stridor

16

++

+++

++

++

13

11

M

63

68

Urinary urgency, stridor

18

ND

ND

ND

ND

ND

ND

12

M

47

49

Erectile dysfunction, orthostatic hypotension

9

++

+

++

22

13

M

63

66

Erectile dysfunction, ortosthatic hypotension, stridor

12

++

++

++

17

UMSARS II Unified Multiple System Atrophy Rating Scale part II, Cb cerebellum, MCP middle cerebellar peduncle, ND not done, Orthostatic hypotension decrease of blood pressure within 3 min of standing by at least 30 mm Hg systolic or 15 mm Hg diastolic

+ Slight, ++ mild, +++ moderate, ++++ severe, − absent

aAge at onset of cerebellar symptoms

Brain MRI showed cerebellar and brainstem atrophy in all 11 patients. The “hot cross bun” sign was present in 9 patients, but in no case was the putaminal “slit-like” sign observed. The mean pontine diameter was 17.6 ± 2.7 mm.

DAT SPECT showed a significant decrease of striatal radiotracer uptake in patients in comparison to controls in all ROIS (p < 0.001). Results of the bilateral quantification of striatal uptake ratios in patients and controls are shown in Table 2. Uptake ratios were within the normal range (≤2 SD of the mean in controls) in three patients (number 2, 3, and 6), one of which fulfilled criteria for probable MSA-C (patient 3). We did not find differences between patients with normal and abnormal uptake ratios in age, disease duration, UMSARS-II score, or pons and cerebellar atrophy severity. There were no significant differences between radiotracer uptake in the right and left sides in the different ROIS. Bilateral binding reduction was 21% for the entire striatum, 24% for the caudate, and 19% for the entire putamen. The difference between caudate and putamen nuclei uptake did not reach statistical significance (p = 0.27).
Table 2

Bilateral specific binding ratios in patients and controls

Subjects

Entire striatum

Caudate

Anterior putamen

Posterior putamen

Entire putamen

Patients

 1

2.36

2.67

2.41

2.01

2.21

 2

2.88a

3.18a

2.83a

2.62a

2.73a

 3

2.64a

3.03a

2.65a

2.22a

2.44a

 4

2.45

2.91a

2.42

2.01

2.22

 5

2.27

2.52

2.28

2.01

2.14

 6

2.72a

3.12a

2.88a

2.14a

2.51a

 7

2.38

2.77

2.45

1.91

2.18

 8

1.71

1.63

1.99

1.52

1.76

 9

1.97

1.48

2.38

2.04

2.21

 10

1.55

1.08

1.89

1.66

1.78

 11

1.95

2.41

1.91

1.55

1.73

 12

2.25

2.88a

2.08

1.80

1.94

 13

2.19

2.54

2.24

1.78

2.01

Mean (±SD)

2.25 (0.38)

2.48 (0.67)

2.34 (0.32)

1.94 (0.3)

2.14 (0.3)

Controls

 1

2.57

2.87

2.52

2.30

2.41

 2

2.81

3.12

2.84

2.48

2.66

 3

2.73

3.01

2.82

2.35

2.59

 4

2.84

3.25

2.87

2.39

2.63

 5

3.01

3.81

2.96

2.25

2.61

 6

3.07

3.49

3.10

2.62

2.86

 7

2.89

3.41

2.90

2.37

2.64

 8

2.74

3.12

2.86

2.25

2.55

 9

2.63

2.98

2.80

2.11

2.45

 10

2.92

3.20

3.04

2.51

2.78

 11

2.95

3.31

2.87

2.65

2.76

 12

3.16

3.64

3.18

2.66

2.92

Mean (±SD)

2.86 (0.18)

3.27 (0.28)

2.90 (0.17)

2.41 (0.18)

2.65 (0.15)

aNormal values in MSA-C patients

No correlation between the striatal uptake ratios and age of patients, UMSARS-II (Fig. 1a), pontine diameter (Fig. 1b), and disease duration (Fig. 1c) were found. However, disease duration correlated with the UMSARS-II score (r = 0.74, p = 0.004) and pontine diameter (r = −0.65, p = 0.031) (Fig. 1d, e).
https://static-content.springer.com/image/art%3A10.1007%2Fs00415-011-6108-8/MediaObjects/415_2011_6108_Fig1_HTML.gif
Fig. 1

Correlation between bilateral entire striatum binding ratios and UMSARS-II (a), pontine diameter (b), and disease duration (c), and between disease duration and UMSARS-II (d) and pontine diameter (e)

Discussion

A total of 13 patients fulfilling diagnostic criteria for possible or probable MSA-C were studied in order to assess whether presynaptic nigrostriatal dopaminergic denervation is a supportive feature for disease diagnosis. Most of our patients had a short disease duration and none of them showed parkinsonian features at the time of imaging. We have found reduced striatal [123I]FP-CIT binding in 10 patients, suggesting the presence of frequent subclinical presynaptic dopaminergic denervation in MSA-C.

Although a number of imaging studies have demonstrated presynaptic dopaminergic system is severely impaired in patients with probable MSA-P [6], there is limited information about nigrostriatal involvement in MSA-C, particularly in cases without parkinsonian signs. A few studies with PET [911] and SPECT [1214] have demonstrated presynaptic dopaminergic denervation in patients diagnosed either with sporadic olivopontocerebellar atrophy (sOPCA) or MSA-C (Table 3). Most of the individuals reported in these previous studies showed parkinsonian signs and, thereby, nigrostriatal dysfunction was an expected feature.
Table 3

Dopamine transporter studies in sporadic OPCA/MSA-C patients

Radiotracer

MSA-C/OPCA patients

Parkinsonism

Striatal uptake (%)a

18F-Dopa9

10 OPCA

No

71

18F-Dopa10

5 OPCA

Yes

79

11C-Dihydrotetrabenazine11

8 MSA-C/6 OPCA

Yes (8)/No (6)

49/78

[123I]β-CIT12

3 MSA-C

Yes

NA

[123I]β-CIT13

9 OPCA

No

69

99mTc-TRODAT-114

19 MSA-C

Yes

70

[123I]FP-CIT (present study)

13 MSA-C

No

79

aFigures are expressed as a percentage of the mean striatal uptake of the respective control group

NA not available

In our study, the mean reduction of the striatal radiotracer uptake was 21%, whereas in previous studies this reduction ranged between 21 and 51% (Table 3). The presence or not of parkinsonism, the different radiotracers used, and the different disease duration of the study subjects could explain the variability between the different studies. Normal striatal uptake in 3 of our patients can also contribute to these differences. We found a similar radiotracer uptake reduction in the caudate and putamen nuclei. As previous studies suggest and in contrast with Parkinson’s disease [10], our findings indicate the presence of homogeneous degeneration of dopaminergic fibers projecting from substantia nigra to both nuclei in MSA-C.

We did not find a correlation between striatal radiotracer binding and clinical cerebellar disability, pontine atrophy in the MRI or disease duration. However, disease duration correlated with cerebellar disability and pontine atrophy. These findings suggest that in MSA-C nigrostriatal denervation and olivopontocerebellar dysfunction may evolve independently and that disease duration correlates with neuronal cell loss in the olivopontocerebellar system. This is in agreement with clinico-pathological studies in MSA that showed a considerable variation of the severity of lesions in both systems [15, 16]. Jellinger et al. [15] reported that only half of the severe OPCA cases studied at autopsy were associated with comparable striatonigral cell loss, whereas low-grade OPCA combined with all degrees of striatonigral degeneration. In addition, Ozawa et al. [16] found that neuronal cell loss in MSA correlated better with disease duration in the olivopontocerebellar system than in the nigrostriatal region.

Although our study has some limitations such as a relatively small number of patients and lack of pathological confirmation, the strict diagnostic criteria that we used for patient inclusion lead us to conclude that subclinical nigrostriatal dopaminergic denervation is common in MSA-C. This gives support to the second consensus criteria statement on the diagnosis of MSA. However, we also consider that normal nigrostriatal dopaminergic innervation, as it was found in 3 of our patients, should not rule out MSA-C.

Conflict of interest

The authors declare that they have no conflict of interest.

Copyright information

© Springer-Verlag 2011