Tau accumulation is associated with dopamine deficiency in vivo in four-repeat tauopathies.

PURPOSE: We hypothesized that severe tau burden in brain regions involved in direct or indirect pathways of the basal ganglia correlate with more severe striatal dopamine deficiency in four-repeat (4R) tauopathies. Therefore, we correlated [18F]PI-2620 tau-positron-emission-tomography (PET) imaging with [123I]-Ioflupane single-photon-emission-computed tomography (SPECT) for dopamine transporter (DaT) availability. METHODS: Thirty-eight patients with clinically diagnosed 4R-tauopathies (21 male; 69.0 ± 8.5 years) and 15 patients with clinically diagnosed α-synucleinopathies (8 male; 66.1 ± 10.3 years) who underwent [18F]PI-2620 tau-PET and DaT-SPECT imaging with a time gap of 3 ± 5 months were evaluated. Regional Tau-PET signals and DaT availability as well as their principal components were correlated in patients with 4R-tauopathies and α-synucleinopathies. Both biomarkers and the residuals of their association were correlated with clinical severity scores in 4R-tauopathies. RESULTS: In patients with 4R-tauopathies, [18F]PI-2620 binding in basal ganglia and midbrain regions was negatively associated with striatal DaT availability (i.e. globus pallidus internus and putamen (ß = - 0.464, p = 0.006, Durbin-Watson statistics = 1.824) in a multiple regression model. Contrarily, [18F]PI-2620 binding in the dentate nucleus showed no significant regression factor with DaT availability in the striatum (ß = 0.078, p = 0.662, Durbin-Watson statistics = 1.686). Patients with α-synucleinopathies did not indicate any regional associations between [18F]PI-2620-binding and DaT availability. Higher DaT-SPECT binding relative to tau burden was associated with better clinical performance (ß = - 0.522, p = 0.011, Durbin-Watson statistics = 2.663) in patients with 4R-tauopathies. CONCLUSION: Tau burden in brain regions involved in dopaminergic pathways is associated with aggravated dopaminergic dysfunction in patients with clinically diagnosed primary tauopathies. The ability to sustain dopamine transmission despite tau accumulation may preserve motor function.

Unexpected (123I)FP-CIT SPECT findings: SWIDD, SWEDD and all DAT.

Although the diagnosis of Parkinson's disease (PD) is essentially clinical, the implementation of imaging techniques can improve diagnostic accuracy. While some techniques (e.g. magnetic resonance imaging-MRI, computerized tomography-CT) are used to exclude secondary syndromes, presynaptic dopaminergic imaging including imaging of dopamine transporter (DAT)-can help the Neurologist in the differential diagnosis between neurodegenerative parkinsonian syndromes and parkinsonism without dopamine deficiency. DAT imaging can be useful in cases in which the clinical picture is not univocal, as in case of overlapping clinical features in patients with early disease, atypical syndromes or unsatisfying response to therapy. Currently, (123I)FP-CIT ([123I]N-ω-fluoropropyl-2ß-carbomethoxy-3ß-(4-iodophenyl)nortropane) (trade name DaTSCAN) is the only agent approved by international regulatory agencies for this purpose. With the increasing use of this technique, some unexpected findings have been reported, including patients clinically diagnosed with PD with a normal SPECT scan [e.g. Scans Without Evidence of Dopaminergic Deficit (SWEDD)]; PD patients with a greater dopaminergic deficit in the striatum ipsilateral to the clinically more affected side [e.g. Scans With Ipsilateral Dopaminergic Deficit (SWIDD)]; as well as some artifacts. Moreover, the neurologist must remember that structural lesions and administration of some drugs might alter the result of DAT imaging. Unexpected findings, artifacts, and misinterpretation of imaging findings can lead to an erroneous diagnosis and inappropriate therapy, neglect of other medical conditions that might explain the clinical picture, and undermine the selection phase in clinical trials. The aim of the present review is to bring clarity on these controversial (and sometimes erroneous) results, in order to inform of these possibilities the clinicians requesting a DaTSCAN in clinical practice.

Low skull bone density is associated with poor motor prognosis in women with Parkinson's disease.

Parkinson's disease (PD) and osteoporosis are degenerative diseases that have shared pathomechanisms. To investigate the associations of skull bone density with nigrostriatal dopaminergic degeneration and longitudinal motor prognosis in female patients with PD. We analyzed the data of 260 drug-naïve female PD patients aged ≥50 years old who were followed-up for ≥3 years after their first visit to the clinic with baseline dopamine transporter (DAT) imaging. We measured skull bone density as a surrogate marker for systemic bone loss by calculating the Hounsfield unit (HU) in computed tomography scans. A Cox proportional hazard model was built to compare the rates of levodopa-induced dyskinesia (LID) or wearing-off according to skull HU. Longitudinal changes in levodopa-equivalent dose (LED) during a 3-year follow-up were assessed using a linear mixed model. A lower skull HU was associated with lower baseline DAT availability in striatal subregions; however, this relationship was not significant after adjusting for age, disease duration, body mass index, and white matter hyperintensities. After adjusting for confounding factors, a lower skull HU was significantly associated with an increased risk of LID development (hazard ratio = 1.660 per 1 standard deviation decrease, p = 0.007) and wearing-off (hazard ratio = 1.613, p = 0.016) in younger (<67 years) but not in older patients. Furthermore, a lower skull HU was associated with a steeper increase in LED during follow-up in younger patients only (ß = -21.99, p < 0.001). This study suggests that baseline skull bone density would be closely linked to motor prognosis in drug naïve women with PD.

Acquisition count dependence of the specific binding ratio in 123I-FP-CIT SPECT.

OBJECTIVE: In the [123I]FP-CIT single-photon emission computed tomography (SPECT) examination, the specific binding ratio (SBR), calculated from the ratio of the striatal specific to extra-striatal background non-specific binding in the brain, is now commonly used as a quantitative index of parkinsonian syndrome. The purpose of this study was to examine the influence of count reduction on the SBR and to clarify the reliability of SBR values in patients with shorter scan times. METHODS: A striatum phantom was used in a phantom study, with the radioactivity concentration adjusted so that the right striatum:left striatum:brain parenchyma ratio was 8:4:1. Changes in SBR values and image quality, expressed as the % coefficient of variation (%CV) and normalized mean squared error (NMSE), with decreasing acquisition counts were evaluated. In the clinical study, 106 patients (73.1 ± 9.6 years) with suspected parkinsonian syndrome underwent [123I]FP-CIT SPECT, and SBR values from normal 30 min acquisitions (fullSBR) and half-count acquisitions (halfSBR) were compared. SBR values were calculated using the Tossici-Bolt (SBRTB) and a fully automatic count-based (SBRcb) methods. RESULTS: In the phantom study, image quality decreased with a reduction of acquisition counts. The %CV and NMSE decreased by up to 52.5% and 81.5%, respectively. SBR values decreased slightly as acquisition counts decreased. In the clinical study, the mean values of halfSBR were lower than those of fullSBR, and they were significantly different except for SBRTB without attenuation correction. halfSBR and fullSBR values correlated well, with halfSBR values 1-8% lower than fullSBR. The accuracy of diagnosis did not decrease even after acquisition counts were reduced by half. CONCLUSION: This study demonstrated that SBR values decrease as a function of reduced acquisition counts. Since halfSBR and fullSBR showed excellent correlation, it is suggested that fullSBR can be estimated from halfSBR using a calibration formula when scan times are reduced.

GCH-1 genetic variant may cause Parkinsonism by unmasking the subclinical nigral pathology.

BACKGROUND: Recent studies suggest that GTP cyclohydrolase 1 (GCH-1) variant may be a risk factor for nigral degeneration causing PD. METHODS: A 49-year-old Korean woman visited our movement disorder clinic with the initial presentation of Parkinsonism starting at age 47. We monitored the degree of nigral degeneration with serial FP-CIT PET throughout the course of her disease (2, 8 and 11 years from disease onset). RESULTS: The initial clinical presentation was consistent with intrinsic dopamine deficiency caused by GCH-1 variant. However, her follow-up disease course was consistent with Parkinsonism caused by nigral neurodegeneration. We found a novel GCH-1 variant in the current case. The disease course of the patient was overall benign in motor and non-motor aspects, corresponding to previously reported GCH-1 cases with PD. Serial FP-CIT PET scans showed normal initial FP-CIT binding followed by a continuous decline of the putaminal binding ratio. However, the decreased binding ratio could not sufficiently explain the corresponding clinical duration of the patient. Therefore, dopamine deficiency by GCH-1 genetic variant contributed to Parkinsonism in the current case with subclinical nigral degeneration. CONCLUSION: Our case suggests that GCH-1 variant causes Parkinsonism by unmasking the subclinical nigral pathology, not by causing the nigral neurodegeneration.

Effect of brain atrophy in quantitative analysis of 123I-ioflupane SPECT.

OBJECTIVE: Dopamine transporter (DAT) imaging such as 123I-ioflupane (123I-FP-CIT) SPECT is a useful tool for the diagnosis of parkinsonism and dementia. The Southampton method is the quantitative method for evaluating 123I-FP-CIT SPECT and is less affected by the partial volume effect of the striatum. The method may be vulnerable to contamination by low-uptake areas of cerebrospinal fluid in whole brain, and the threshold of voxel value (threshold method, TM) was developed to correct the contamination. The purpose of this study is to evaluate the TM in the patients with neurological disease. METHODS: We studied 99 subjects, including 39 patients with Alzheimer's disease (AD), 15 patients with Parkinson's disease (PD) and 10 patients with dementia with Lewy bodies (DLB). Each subject had undergone 123I-FP-CIT SPECT. We calculated the SBR with and without the TM. The SBR laterality was assessed using the asymmetry index (AI). We investigated the relationship between the SBR change with TM and brain atrophy, which were assessed using Evans index (EI), sylvian index (SI) and cerebral atrophy index (CAI). Cutoff value for EI was 0.3, and cutoff values for SI and CAI were the first quartile, respectively. RESULTS: The SBR with TM was 0.53 percentage points lower than the SBR without TM overall (p < 0.01). Positive and negative reversal of AI increased with age. The rate of the SBR change with TM was tended to be lower in groups with brain atrophy. The number of voxels excluded by TM in striatal volumes of interest (VOIs) was larger with high groups for EI, SI and CAI than in low groups. The number of voxels excluded using TM in reference VOIs was related to SI. CONCLUSIONS: The SBR was decreased using TM. The effect of TM on the SBR tended to be small in the subjects with severe brain atrophy. The effect of brain atrophy in the TM is larger in the striatal VOIs than in the reference VOIs. Even if quantitative analyses are available, visual assessment of 123I-FP-CIT SPECT is essential for diagnosis.

Progressive spasticity, supranuclear gaze palsy and postural instability, without parkinsonism: what's in a phenotype?

We present a series of patients with vertical supranuclear gaze palsy, postural instability with falls, and progressive spasticity, who mimic Progressive Supranuclear Palsy - Richardson's syndrome (PSP-R) but have no parkinsonism, and in whom dopamine transporter imaging is normal. We suggest possible aetiologies for this constellation of symptoms, discuss the possible origin of these signs and highlight this phenotype as it may mimic atypical parkinsonism and in particular PSP.

Novel GCH1 variant in Dopa-responsive dystonia and Parkinson's disease.

BACKGROUND: GTP cyclohydrolase I (GCH1) mutations are the commonest cause of Dopa-responsive dystonia (DRD). Clinical phenotypes can be broad, even within a single family. METHODS: We present clinical, genetic and functional imaging data on a British kindred in which affected subjects display phenotypes ranging from DRD to Parkinson's disease (PD). Twelve family members were studied. Clinical examination, dopamine transporter (DAT) imaging, and molecular genetic analysis of GCH1 and the commonest known familial PD-related genes were performed. RESULTS: We have identified a novel missense variant, c.5A > G, p.(Glu2Gly), within the GCH1 gene in affected family members displaying a range of phenotypes. Two affected subjects carrying this variant had abnormal DAT imaging. These two with abnormal DAT imaging had a PD phenotype, while the remaining three subjects with the novel GCH1 variant had normal DAT imaging and a DRD phenotype. CONCLUSIONS: We propose that this GCH1 variant is pathogenic in this family and these findings suggest that similar mechanisms involving abnormal GTP cyclohydolase I may underlie both PD and DRD. GCH1 genetic testing should be considered in patients with PD and a family history of DRD.

The semicolon sign: dopamine transporter imaging artifact from head tilt.

Dopamine transporter (DAT) imaging is a valuable tool to aid in the diagnosis of Parkinson disease and other Parkinsonian syndromes. DAT imaging is special among clinical nuclear medicine scans in that the already small caudate and putamen are presented in multiple thin axial cuts. Because the imaged basal ganglia are small, slight differences in head tilt may result in a significant artifact that we have termed the semicolon sign. The semicolon sign occurs when forward head tilt creates select images that show the caudate nuclei separate from the putamen. This gives the false impression that DAT activity in the putamen is decreased or absent. To avoid falsely attributing this artifact to loss of putaminal activity, it is imperative that the interpreting physician first recognize the artifact and then mentally integrate all provided images to identify normal activity in the putamen on subsequent levels. Furthermore, quantitative software packages for automated DAT scan interpretation are now available. If images demonstrating the semicolon sign are used for automated interpretation, loss of activity in the putamen may be falsely calculated, thereby contributing to erroneous results. Quality control measures are essential to ensure that technologists correctly position each patient's head to minimize head tilt artifact on DAT scan images. A protocol to obtain optimal head positioning is presented.