Abstract
Background:
Corticobasal degeneration (CBD) is characterized by neuronal and glial deposition of 4-repeat tau in the frontal and parietal cerebral cortex, white matter and striatum. There is neuronal loss in affected cortical regions and in the substantia nigra (SN). Recent single photon emission tomography (SPECT) studies have reported normal striatal dopamine transporter (DAT) binding in individual patients with CBD.
Objective:
To study the pattern and course of DAT binding loss in CBD.
Methods:
We retrospectively analyzed DAT SPECT studies in two patients presenting with a corticobasal syndrome in whom a diagnosis of CBD was later confirmed pathologically.
Results:
Baseline scans at 1.5 years after symptom onset revealed only mild abnormalities (reduced uptake in one putamen). Follow up scans at 4.5 years (Case 1) and 5 years (Case 2) after symptom onset showed a marked decline of striatal DAT binding. In both cases, there was a 37% binding reduction from the age-expected striatal binding value. Asymmetry of striatal DAT binding had increased from mild in the first SPECT studies to moderate at the time of their final imaging.
Conclusion:
CBD patients can have delayed neuronal loss in the SN. Follow up DAT imaging may be of value in patients with possible CBD and a normal baseline scan.
Keywords
INTRODUCTION
Corticobasal degeneration (CBD) is a rare, sporadic neurodegenerative disease characterized by cortical and basal ganglia dysfunction and focal atrophy involving the frontal and parietal lobes [1]. At a molecular level, CBD belongs to the class of primary 4-repeat tauopathies and shows similarities to progressive supranuclear palsy (PSP) [2]. The neuropathological diagnosis of CBD rests on the presence of tau-positive cortical and striatal neuronal and glial lesions, especially astrocytic plaques and neuronal threads, in both white and gray matter combined with neuronal loss in affected cortical regions and the substantia nigra [3].
The clinical phenotype usually associated with CBD comprises asymmetric, rigid-akinetic, levodopa-resistant parkinsonism, limb dystonia and cortical signs such as apraxia and cortical sensory loss. But clinicopathological correlation is inconsistent and the term “corticobasal syndrome” (CBS) is preferable [4]. CBD pathology can be associated with a range of other clinical phenotypes including the behavioural variant of frontotemporal dementia and progressive non-fluent aphasia [4]. On the other hand, the CBS phenotype can be caused by a spectrum of different pathologies including other frontotemporal lobar degenerations and Alzheimer’s disease [4]. Only about one quarter to one half of the patients with CBS have histopathological changes of CBD atautopsy [5–10].
Imaging of the presynaptic dopaminergic system with [18F]fluorodopa positron emission tomography (F-Dopa PET) and dopamine transporter single photon emission computerized tomography (DAT SPECT) have been used to document nigrostriatal degeneration in CBS [11–17]. While earlier studies pointed towards a high sensitivity of presynaptic imaging in CBS, a recent [123I]FP-CIT SPECT study found normal striatal uptake in part of the patients [17]. Striatal [123I]FP-CIT binding was also reported to be normal in three cases with pathology-confirmedCBD [18–20].
We report on DAT imaging findings in two CBD cases (both with a CBS phenotype) and, for the first time, provide data on the course of nigrostriatal dopaminergic degeneration in pathologically verified CBD which may explain the discrepancies in previous studies between imaging and pathology.
PATIENTS AND METHODS
Subjects
The present study is part of a larger research project aiming at validation of dopaminergic imaging by retrospective analysis of DAT SPECT examinations in movement disorder patients with definite post-mortem diagnoses [21, 22]. From a group of 25 patients who had undergone DAT imaging using the same imaging protocol and subsequently underwent detailed neuropathological evaluation, two male patients with CBS and a post-mortem diagnosis of CBD were selected. Another patient with CBS but multiple system atrophy (MSA) on pathology [21] was excluded from the present study. The study protocol was approved by the ethics review board of the Medical University of Vienna.
Case 1 developed left-sided clumsiness, unsteadiness of gait, mental slowing and forgetfulness at the age of 64 years. One year after symptom onset, magnetic resonance imaging showed right frontoparietal atrophy. His left-predominant rigid-akinetic parkinsonism did not respond to levodopa. He developed limb apraxia, fixed flexion dystonia of the left upper limb and progressed to frontal dementia. He became bed-ridden with severe spastic tetraparesis and died5 years after onset.
Case 2 developed progressive clumsiness and difficulties with concentration at the age of 63 years. When first examined one year after symptom onset, he showed mild cognitive impairment, mild rigidity, motor slowing without true bradykinesia and non-specific clumsiness, most pronounced in the left upper limb. Magnetic resonance imaging showed subtle right-predominant frontoparietal atrophy. Two years after onset, the patient noted that his left hand had “a life of its own”. He showed marked ideomotor apraxia, cortical sensory loss, a mild rigid-aktinetic syndrome and dystonia, more pronounced in the left limbs. Levodopa had no beneficial effect. His gait became progressively apraxic. Seven years after onset he became bed-ridden and died from aspirationpneumonia.
Both underwent DAT SPECT 1.5 years after symptom onset. During follow-up, SPECT investigations were repeated on a clinical basis, in case 1 at 4.5 years after onset, in case 2 at 3 and 5 years after symptom onset. Overall striatal binding values from the last SPECT imaging in both cases have been published as part of a study correlating striatal DAT binding with substantia nigra cell counts [22].
SPECT imaging
All SPECT examinations were performed with the same triple-headed gamma camera according to a standard protocol described previously [21, 22]. [123I]β-CIT served as DAT ligand. SPECT data acquisition was carried out 20 hours after tracer application.
Neuropathology
Neuropathological examination was performed in both patients as described previously [21, 22].Both fulfilled neuropathological criteria for CBD [3]. Abundant thread-like-structures in the grey andwhite matter were noted in the frontal, cingular and parietal cortex, as well as the basal ganglia. Astrocytic plaques, oligodendroglial coiled bodies and numerous neurons showing diffuse granular cytoplasmic immunoreactivity for tau were observed in the same cortical regions and the basal ganglia. Neuronal loss was evident in cortical regions. Both brains showed a comparable degree of neuronal tau pathology and overall moderate cell loss in the substantia nigra. In both, neuronal loss in the substantia nigra was more prominent contralateral to the clinically more affected limbs.
RESULTS
Representative axial SPECT images from both cases and a healthy control subject are presented in Fig. 1. Results of the semiquantitative SPECT analysis are displayed in Table 1. Visual inspection of the baseline scan in case 1 revealed reduced uptake in the right putamen but normal DAT binding in the left striatum. The follow up scan showed a marked decline of striatal DAT binding with moderately asymmetric, oval-shaped uptake typical of advanced parkinsonism. In case 2, the baseline scan showed reduced uptake in the right putamen and a possible DAT binding reduction in the left posterior putamen. The follow up scans revealed progressive decline of DAT binding, especially in the right striatum, which developed a more circular appearance.
Semiquantification indicated only minor DAT binding loss at baseline, with left striatal binding in Case 1 close to the age-expected value (Table 1). During the follow up period DAT binding, averaged over the right and left striatum, declined by 30.9% , resulting in a binding reduction of 36.7% from age-expected striatal binding at 4.5 years after symptom onset. In Case 2, the decline of binding, averaged over the right and left striatum, over the whole follow up period of 3.5 years was 25.1% , amounting in a binding reduction of 37.2% from age-expected striatal DAT binding after a disease duration of 5 years. Asymmetry of striatal DAT binding tended to increase from mild at the time of the first SPECT imaging to moderate at the time of last imaging (Table 1).
DISCUSSION
Neuronal loss in the SN is regarded as a core pathologic feature of CBD [3]. While some studies have pointed towards a high sensitivity of dopaminergic nerve terminal imaging in CBS [11–16], a recent [123I]FP-CIT SPECT study involving 36 patients found normal striatal uptake in four and only unilateral striatal binding reduction in another four patients [17]. Striatal FP-CIT binding was also found to be normal in three cases with pathology-confirmed CBD [18–20]. The first case was diagnosed with dementia with Lewy bodies but had CBD variant pathology [18]. The second case presented with a CBS, underwent DAT imaging 4 years after symptom onset and died after a 10 years disease course. Striatal DAT binding was unequivocally normal. Neuropathology showed severe neuronal loss in the substantia nigra [19]. In the third case, also with a CBS phenotype, a DAT SPECT study was performed 9 months after symptom onset. Semiquantification yielded normal striatal uptake. However, striatal binding appeared asymmetric on visual inspection and the published images suggest mild diffuse binding reduction in the right striatum. The patient died 3.5 years after onset. Neuropathology showed neuronal loss in theSN [20].
The results of our study are in line with these findings. Both of our CBD cases were first imaged 1.5 years after symptom onset and their scans showed only mild, unilateral striatal binding reduction, similar to the case presented by Kaasinen et al. [20]. Such minor abnormalities of striatal uptake may be easily mistaken as mild normal anatomical asymmetry [23]. By contrast, patients with Parkinson’s disease usually show a clear-cut bilateral striatal binding reduction, even at a stage when clinical signs are still strictly unilateral [23]. Likewise, patients with MSA and PSP typically show a bilateral reduction of striatal DAT binding, preferentially affecting the putamen. Consequently DAT imaging cannot differentiate between these three common forms of degenerative parkinsonism [23].
The follow up scans in both of our CBD cases showed a marked decline of striatal DAT binding over time with a change of the shape of striatal uptake to a more oval or circular form, typical of advanced parkinsonism [23]. A similar progressive decline of striatal binding from normal to bilaterally reduced was recently reported for 4 CBS patients with baseline FP-CIT SPECT imaging between 1 and 4 years after symptom onset and follow up imaging after 1 to 2 years [24].
The striatal DAT binding reduction of about 35% from age-expected striatal binding at approximately 5 years after symptom onset in our 2 CBD cases is within the range observed in patients with hemi-PD [25] and thus somewhat less marked than in PD of similar duration. Though dopaminergic degeneration is regarded as a core pathologic feature of CBD [3], a recent pathological study demonstrated that in CBD patients with a CBS phenotype, cell loss in the ventrolateral SN is less severe and more variable than in CBD patients with a Richardson’s syndrome phenotype and in Richardson’s syndrome patients with PSP pathology [26]. In contrast to Richardson’s syndrome patients with CBD or PSP pathology, CBD patients with the CBS phenotype show much more severe tau pathology in the primary motor cortex and putamen, [26] which may determine the clinical phenotype regardless of the degree of neurodegeneration in the SN.
The asymmetry of striatal DAT binding in our CBD cases was mild to moderate and well within the range observed in patients with post mortem confirmed PD [21]. Imaging studies in CBS patients without pathological confirmation found more asymmetry of striatal DAT binding compared with PD [17]. In our retrospective [123I]β-CIT SPECT study of 25 patients with various forms of parkinsonism who came to autopsy, marked striatal binding asymmetry was exclusively observed in MSA. One of our MSA patients with marked striatal asymmetry had been misdiagnosed with CBD [21], illustrating the potential bias in imaging studies without pathological confirmation.
In conclusion, our study confirms that while DAT SPECT may be normal or only mildly abnormal in early CBD, there may be progressive decline of striatal binding on follow up imaging. In clinical practice, CBD may be one potential underlying pathology in a patient with suspected degenerative parkinsonism and a normal or near normal striatal DAT imaging result. Follow up DAT imaging may be of value in patients with possible CBD and a normal baseline scan.
Conflict of interest
The authors have no conflict of interest to declare.
Footnotes
ACKNOWLEDGMENTS
We thank A/Prof. Peter A. Kempster, Departement of Neuroscience, Monash Medical Centre, Clayton, Victoria, Australia, for proofreading the manuscript.