Striatal Dopamine Transporter Uptake Research Articles

Fractional Anisotropy and Mean Diffusion as Measures of Dopaminergic Function in Parkinson's Disease: Challenging Results.

Diffusion tensor imaging (DTI) has been purported as an imaging technique to assess dopaminergic degeneration in Parkinson's disease. To test if fractional anisotropy (FA) and mean diffusion (MD) in the basal ganglia as measured by DTI correlates with dopaminergic function as measured by dopamine transporter (DAT) and dopamine D2-receptor (D2R) SPECT. One-hundred and eleven patients with Parkinson's disease (71±10years) and thirty-one controls (68±7years) performed DTI, DAT and D2R SPECT at baseline and four follow-ups (1-year: 89 patients/zero controls; 3-year: 72/11; 5-year: 48/17; and 8-year: 13/13). Four equipment combinations of MRI scanners/SPECT gamma cameras were used during the study. Data from each combination were analyzed separately. Regions-of-interest were outlined in the substantia nigra (three subareas, DTI only) and in the striatum (putamen and caudate). Side differences and bilateral averages were correlated using linear regression. The significance threshold was set at P < 0.001 and 0.001 < P< 0.05 was defined as atrend towards significance. For side differences, no significant correlations were observed, but in patients, there was atrend towards anegative correlation between MD in the middle nigra and putaminal DAT uptake in two combinations (P = 0.04 and P = 0.03). For averages, in patients, striatal MD correlated negatively with striatal DAT uptake in one combination (P = 0.0005) and trended towards negative correlations with striatal D2R uptake (one combination, P = 0.03) and with the sum of striatal DAT and D2R uptake (two combinations P = 0.002 and P = 0.03). FA showed no correlations in patients, and no correlations were found in controls. The poor correlations between MD and dopamine activity -and absent correlations for FA - imply that additional diffusion measures must be developed to reliably assess the dopaminergic degeneration in Parkinson's disease.

Peripheral leukocyte apoptosis in patients with Parkinsonism: correlation with clinical characteristics and neuroimaging findings.

Apoptosis of both brain neurons and peripheral blood leukocyte is believed to be an important biomarker for evaluating the functional status of Parkinson's disease (PD). However, their correlation remains unknown. A better understanding of the pathophysiology of neurodegeneration is essential for the treatment and prevention of PD. The present study demonstrated that leukocyte apoptosis is significantly higher in PD patients and is associated with central dopamine neuron loss by using 99mTc-TRODAT-1 SPECT. The leukocyte apoptosis and striatal dopamine transporter uptake ratios were further associated with increased severity and longer duration of disease. The interaction between brain and systemic inflammation may be responsible for the neurodegenerative disease progression.

Decreased striatal dopamine transporter uptake in the non‐fluent/agrammatic variant of primary progressive aphasia

Patients with the non-fluent/agrammatic variant of primary progressive aphasia (nfvPPA) may develop atypical parkinsonian syndromes. However, there is no current biomarker to assess which patients are at high risk of developing parkinsonism. 123I-2β-carbomethoxy-3β-(4-iodophenyl)-N-(3-fluoropropyl)-nortropane (123I-FP-CIT)-SPECT detects striatal dopamine dysfunction in vivo. The objective of the present study was to study whether non-fluent/agrammatic patients without parkinsonism at baseline present decreased striatal 123I-FP-CIT uptake. Visual and semi-quantitative assessments of the striatal 123I-FP-CIT uptake ratio were carried out in 15 patients with nfvPPA, eight patients with the logopenic variant of PPA (lvPPA) and 18 controls. To rule out progranulin mutations or underlying Alzheimer's disease (AD), serum progranulin levels and cerebrospinal fluid (CSF) biomarkers of AD (Aβ42 , total-tau, phosphorylated-tau181 ) were determined. A second 123I-FP-CIT-SPECT analysis in the biomarker-enriched groups was also carried out. Patients with nfvPPA presented reduced striatal 123I-FP-CIT binding, especially in the left hemisphere (P = 0.002), compared with controls. All lvPPA patients had normal striatal 123I-FP-CIT uptake. 123I-FP-CIT striatal binding in nfvPPA patients with normal progranulin and CSF biomarker levels (nfvPPA/bio-) was also significantly reduced (P < 0.05) compared with lvPPA patients with positive AD biomarkers. Sixty-four per cent (9/14) of nfvPPA patients and 80% of nfvPPA/bio- patients (8/10) showed a diminished individual left striatal 123I-FP-CIT uptake ratio. On follow-up, seven nfvPPA/bio- patients developed parkinsonism (median 1.9 years; range 1.2-2.9), six of them with baseline reduced 123I-FP-CIT uptake. Reduced striatal tracer uptake in nfvPPA patients prior to clinical parkinsonism can be detected by 123I-FP-CIT-SPECT, especially in those with nfvPPA/bio-, suggesting subclinical nigrostriatal degeneration. Decreased striatal 123I-FP-CIT binding might identify PPA patients at increased risk of developing atypical parkinsonian syndromes, probably related to tau-pathology.

Neurodegenerative disease status and post-mortem pathology in idiopathic rapid-eye-movement sleep behaviour disorder: an observational cohort study

We postulated that idiopathic rapid-eye-movement (REM) sleep behaviour disorder (IRBD) represents the prodromal phase of a Lewy body disorder and that, with sufficient follow-up, most cases would eventually be diagnosed with a clinical defined Lewy body disorder, such as Parkinson's disease (PD) or dementia with Lewy bodies (DLB). Patients from an IRBD cohort recruited between 1991 and 2003, and previously assessed in 2005, were followed up during an additional period of 7 years. In this original cohort, we sought to identify the nature and frequency of emerging defined neurodegenerative syndromes diagnosed by standard clinical criteria. We estimated rates of survival free from defined neurodegenerative disease by means of the Kaplan-Meier method. We further characterised individuals who remained diagnosed as having only IRBD, through dopamine transporter (DAT) imaging, transcranial sonography (TCS), and olfactory testing. We did a neuropathological assessment in three patients who died during follow-up and who had the antemortem diagnosis of PD or DLB. Of the 44 participants from the original cohort, 36 (82%) had developed a defined neurodegenerative syndrome by the 2012 assessment (16 patients were diagnosed with PD, 14 with DLB, one with multiple system atrophy, and five with mild cognitive impairment). The rates of neurological-disease-free survival from time of IRBD diagnosis were 65·2% (95% CI 50·9 to 79·5) at 5 years, 26·6% (12·7 to 40·5) at 10 years, and 7·5% (-1·9 to 16·9) at 14 years. Of the four remaining neurological-disease-free individuals who underwent neuroimaging and olfactory tests, all four had decreased striatal DAT uptake, one had substantia nigra hyperechogenicity on TCS, and two had impaired olfaction. In three patients, the antemortem diagnoses of PD and DLB were confirmed by neuropathological examination showing widespread Lewy bodies in the brain, and α-synuclein aggregates in the peripheral autonomic nervous system in one case. In these three patients, neuronal loss and Lewy pathology (α-synuclein-containing Lewy bodies and Lewy neurites) were found in the brainstem nuclei that regulate REM sleep atonia. Most IRBD individuals from our cohort developed a Lewy body disorder with time. Patients who remained disease-free at follow-up showed markers of increased short-term risk for developing PD and DLB in IRBD, such as decreased striatal DAT binding. Our findings indicate that in most patients diagnosed with IRBD this parasomnia represents the prodromal phase of a Lewy body disorder. IRBD is a candidate for the study of early events and progression of this prodromal phase, and to test disease-modifying strategies to slow or stop the neurodegenerative process. None.

Is 6 Months of Neuroleptic Withdrawal Sufficient to Distinguish Drug-Induced Parkinsonism From Parkinson's Disease?

ABSTRACTBackground: Drug-induced parkinsonism (DIP) is the second commonest cause of akinetic-rigid syndrome in the western world. Differentiating DIP from Parkinson's disease (PD) may be a challenge to clinicians. One of the factors distinguishing DIP from PD is that discontinuation of the neuroleptic agent in DIP should relieve the symptoms of parkinsonism. The majority of the literature uses the 6-month timeframe between the neuroleptic withdrawal and resolution of the symptoms of parkinsonism. Methods: We report two cases of DIP wherein the symptoms of parkinsonism persisted more than 6-months from withdrawal of the dopamine receptor blocking agent (DRBA) and the results of their ioflupane iodine-123 (DaT) single-photon emission computed tomography (SPECT) scan. DaT scan is a newly approved radiopharmaceutical in the United States indicated for striatal dopamine transporter visualization to assist in the evaluation of adult patients with suspected parkinsonian syndromes. Results: The first case is a patient who developed parkinsonism from risperidone, while the second case developed parkinsonism from metoclopramide. In both cases, parkinsonism persisted 6 months after discontinuation of the DRBA, therefore DaT scan was obtained, showing normal striatal dopamine transporter uptake. Nine months after the discontinuation of the DRBA, parkinsonism was significantly improved in both patients but not completely resolved. Conclusion: Our two cases illustrate the possibility of persistent parkinsonism beyond 6–9 months from the time of neuroleptic withdrawal without evidence of presynaptic dopaminergic neuronal loss that would be suggestive of conversion to PD. We recommend that the official recommendation of the minimum time of neuroleptic withdrawal be modified to at least 1 year before entertaining the diagnosis of PD conversion in patients with exposure to DRBAs.

Orthostatic hypotension, non-dipping and striatal dopamine in Parkinson disease

Orthostatic hypotension and non-dipping are relatively common autonomic dysfunctions in patients with Parkinson disease (PD). These abnormalities have been thought to occur independently of striatal dopaminergic depletion; however, only little preliminary information is available. In this study, we investigated the association of neurocirculatory changes with striatal dopamine transporter status in 69 patients with early PD. Seventeen patients had orthostatic hypotension and 55 patients were non-dippers. A comparison between cases with and without orthostatic hypotension was insignificant for striatal dopamine transporter uptake. These insignificances continued in a comparison of dippers and non-dippers. These results suggest that sympathetic noradrenergic dysfunctions in PD are independent of striatal dopamine transporter depletion.

Decreased striatal dopamine transporter uptake and substantia nigra hyperechogenicity as risk markers of synucleinopathy in patients with idiopathic rapid-eye-movement sleep behaviour disorder: a prospective study

Patients with idiopathic rapid-eye-movement sleep behaviour disorder (IRBD) may develop neurodegenerative conditions associated with substantia nigra dysfunction such as Parkinson's disease. In patients with Parkinson's disease, ¹²³I-2β-carbomethoxy-3β-(4-iodophenyl)-N-(3-fluoropropyl)-nortropane (¹²³I-FP-CIT) SPECT detects striatal dopamine dysfunction resulting from nigral pathology whereas transcranial sonography (TCS) shows increased substantia nigra echogenic size, even before parkinsonism is clinically evident. We postulated that these neuroimaging changes could occur in a proportion of IRBD individuals who might then be at increased risk for development of a neurodegenerative disorder associated with substantia nigra dysfunction. In our prospective study, we identified patients with IRBD from individuals referred to our sleep disorders centre in Barcelona, Spain. At baseline, we assessed dopamine transporter [corrected] uptake by use of ¹²³I-FP-CIT SPECT, and estimated echogenicity of the substantia nigra by use of TCS. After a follow-up of 2·5 years, participants were clinically assessed to establish whether they had developed neurodegenerative syndromes. Data were compared with those of matched healthy controls. 43 individuals with IRBD agreed to participate in the study. We found reduced ¹²³I-FP-CIT binding in the striatum (p=0·045) in 17 (40%) of 43 participants compared with 18 controls, and substantia nigra hyperechogenicity in 14 (36%) of 39 participants with IRBD, compared with 16 (11%) of 149 controls (p=0·0002). Tracer uptake reduction was more pronounced in the putamen than it was in the caudate nucleus. 27 (63%) participants had reduced ¹²³I-FP-CIT binding or substantia nigra hyperechogenicity at baseline. Eight (30%) of these participants developed a neurodegenerative disorder (five Parkinson's disease, two dementia with Lewy bodies, and one multiple system atrophy). Individuals with normal neuroimaging results remained disease-free. Sensitivity of combined ¹²³I-FP-CIT SPECT and TCS to predict conversion to synucleinopathy after 2·5 years was 100% and specificity was 55%. In patients with IRBD, ¹²³I-FP-CIT SPECT and TCS can detect subclinical changes much the same as those typically seen in patients with early Parkinson's disease. Decreased striatal ¹²³I-FP-CIT binding and substantia nigra hyperechogenicity might be useful markers to identify individuals at increased risk for development of synucleinopathies. None.

I10 In vivo evidence of decreased nigrostriatal terminals in Huntington's disease: a SPECT study

BackgroundHuntington's disease (HD) is pathologically characterised by a selective neurodegeneration of vulnerable populations of neurons, with an early marked neuronal loss and atrophy in the neostriatum. Dopaminergic innervations of neostriatal...