Rhinorrhea is increased in Parkinson's disease

We have observed that rhinorrhea is increased in people with Parkinson's disease (PD) but only a single publication supports this. We performed two separate case control studies to assess the prevalence of rhinorrhea in PD in Rhode Island. One was cross‐sectional and the other in consecutive de novo patients. We further questioned subjects as to whether rhinorrhea might be associated with olfactory impairment. We found that rhinorrhea affects about half of PD patients in Rhode Island, is an early feature, being present at the time of presentation, was significantly more common than in controls and was associated with self‐perceived reduced olfaction. These observations confirm that rhinorrhea is a common problem and raise the questions as to whether some olfactory impairment found in PD could be confounded by rhinorrhea and also whether rhinorrea may be a premotor symptom. © 2007 Movement Disorder Society     

Presynaptic dopaminergic function in patients with restless legs syndrome: Are there common features with early Parkinson's disease?

The cause of restless legs syndrome (RLS) is unknown, but an involvement of the dopaminergic system and a possible relation to Parkinson's disease (PD) is suggested by the positive response to dopaminergic treatment. We imaged the striatal dopamine transporter with [(123)I] N-(3-iodopropen-2-yl)-2beta-carbomethoxy-3beta-(chloro-phenyl) tropane ([(123)I]IPT) and single-photon emission computed tomography (SPECT) in 28 RLS patients, and compared the results with transporter binding in 29 patients with early PD and 23 age-matched controls. No difference in IPT binding was found between RLS patients and controls. IPT binding was correlated significantly with age in RLS patients and controls, whereas there was no relation with the duration of symptoms or severity of RLS. PD patients presented significant lower presynaptic IPT binding ipsi- and contralateral to the affected body side compared with RLS patients or controls. We found no common characteristics between RLS patients and patients with early PD detectable by dopamine transporter SPECT. Our results do not strengthen an identical pathophysiologic pathway between RLS and PD on the level of nigrostriatal presynaptic terminal function.     

Parkinson's disease and aging: Same or different process?

Parkinson's disease (PD), which probably commences in the olfactory bulb and nuclei of IX and X, may represent accelerated normal aging or a disease specific process. The olfactory and motor disorders are associated in PD, so that smell loss should reflect the underlying disease course. Information on age‐associated decline can be obtained by single measurement from cross‐sectional analysis of patients and controls of different ages, because the observed between‐subject picture may reflect a similar within‐subject pattern. University of Pennsylvania Smell Identification Test (UPSIT) scores were examined for aging effects in 263 controls and 266 PD patients. Three models were applied that are (a) simple linear regression and (b) quadratic term in age: (i) assuming two parallel curves and (ii) allowing for two separate curves. Both groups declined with age. All three models were fitted successfully to the cross‐sectional data and none suggested that the lower mean UPSIT score in patients compared to controls was a premature ageing effect. The mean PD‐UPSIT score even at the age of 40, was lower than the control mean at the upper life‐span limit, implied that the decline in olfaction in PD is faster than simple aging. Extrapolation back in time suggested onset before birth, which is unlikely and implies that at some point there is a more rapid decline than observed in this sample. On the basis of olfactory measurement, our data are consistent with the proposal that PD starts as an acute event, followed by further disease progression more rapid than simple aging. © 2007 Movement Disorder Society     

Dopaminergic innervation of the human striatum in Parkinson's disease.

In Parkinson's disease (PD), dopaminergic input to the caudate nucleus and a band of putaminal tissue abutting the external globus pallidus seems well preserved on immunohistochemical staining for the dopamine transporter. Counting of dopaminergic terminals showed that terminal density in these regions in PD was the same as that in controls, which indicates that input is truly preserved and not a consequence of a compensatory upregulation of metabolism in a reduced pool of surviving terminals. When the branching pattern of dopaminergic axons coursing through the globus pallidus was examined, we found no evidence for increased axonal sprouting in PD that might have contributed to preservation of dopaminergic input to the putamen or caudate nucleus. Although terminal counting indicated that anatomic input was preserved to parts of the striatum, dopamine uptake site density in these regions was reduced significantly. This suggests that the impact of disease in these areas is more profound than was thought previously.     

Dopaminergic correlates of metabolic network activity in Parkinson's disease

Parkinson's disease (PD) is associated with distinct metabolic covariance patterns that relate to the motor and cognitive manifestations of the disorder. It is not known, however, how the expression of these patterns relates to measurements of nigrostriatal dopaminergic activity from the same individuals. To explore these associations, we studied 106 PD subjects who underwent cerebral PET with both ¹⁸F‐fluorodeoxyglucose (FDG) and ¹⁸F‐fluoro‐L‐dopa (FDOPA). Expression values for the PD motor‐ and cognition‐related metabolic patterns (PDRP and PDCP, respectively) were computed for each subject; these measures were correlated with FDOPA uptake on a voxel‐by‐voxel basis. To explore the relationship between dopaminergic function and local metabolic activity, caudate and putamen FDOPA PET signal was correlated voxel‐wise with FDG uptake over the entire brain. PDRP expression correlated with FDOPA uptake in caudate and putamen (P < 0.001), while PDCP expression correlated with uptake in the anterior striatum (P < 0.001). While statistically significant, the correlations were only of modest size, accounting for less than 20% of the overall variation in these measures. After controlling for PDCP expression, PDRP correlations were significant only in the posterior putamen. Of note, voxel‐wise correlations between caudate/putamen FDOPA uptake and whole‐brain FDG uptake were significant almost exclusively in PDRP regions. Overall, the data indicate that PDRP and PDCP expression correlates significantly with PET indices of presynaptic dopaminergic functioning obtained in the same individuals. Even so, the modest size of these correlations suggests that in PD patients, individual differences in network activity cannot be explained solely by nigrostriatal dopamine loss. Hum Brain Mapp 36:3575–3585, 2015. © 2015 Wiley Periodicals, Inc.     

Dopamine transporter imaging is associated with long‐term outcomes in Parkinson's disease

Dopamine (DA) transporter (DAT) imaging has been studied as a diagnostic tool for degenerative parkinsonism. Our aim was to measure the prognostic value of imaging for motor and nonmotor outcomes in Parkinson's disease (PD). We prospectively evaluated a Parkinson's cohort after enrollment in a de novo clinical trial with a battery of motor (UPDRS), cognitive (Montreal Cognitive Assessment), and behavioral measures. DAT imaging with [¹²³I][β]‐CIT and single‐photon emission computerized tomography (SPECT) was performed at baseline and after 22 months. In total, 491 (91%) of the 537 subjects had evidence of DA deficiency on their baseline scan, consistent with PD, and were included in the analyses. The cohort was followed for 5.5 (0.8) years, with a mean duration of diagnosis of 6.3 (1.2). Lower striatal binding at baseline was independently associated with higher risk for clinical milestones and measures of disease severity, including motor‐related disability, falling and postural instability, cognitive impairment, psychosis, and clinically important depressive symptoms. Subjects in the bottom quartile for striatal binding, compared to the top quartile, had an odds ratio (95% confidence interval) of 3.3 (1.7, 6.7) for cognitive impairment and 12.9 (2.6, 62.4) for psychosis. Change from baseline in imaging after 22 months was also independently associated with motor, cognitive, and behavioral outcomes. DAT imaging with [¹²³I][β]‐CIT and SPECT, shortly after the diagnosis of PD, was independently associated with clinically important long‐term motor and nonmotor outcomes. These results should be treated as hypothesis generating and require confirmation. © 2012 Movement Disorder Society     

Reduced dopamine transporter binding predates impulse control disorders in Parkinson's disease

Impulse control disorders (ICD) are relatively common in Parkinson's disease (PD) and generally are regarded as adverse effects of dopamine replacement therapy, although certain demographic and clinical risk factors are also involved. Previous single‐photon emission computed tomography (SPECT) studies showed reduced ventral striatal dopamine transporter binding in Parkinson patients with ICD compared with patients without. Nevertheless, these studies were performed in patients with preexisting impulse control impairments, which impedes clear‐cut interpretation of these findings. We retrospectively procured follow‐up data from 31 medication‐naïve PD patients who underwent dopamine transporter SPECT imaging at baseline and were subsequently treated with dopamine replacement therapy. We used questionnaires and a telephone interview to assess medication status and ICD symptom development during the follow‐up period (31.5 ± 12.0 months). Eleven patients developed ICD symptoms during the follow‐up period, eight of which were taking dopamine agonists. The PD patients with ICD symptoms at follow‐up had higher baseline depressive scores and lower baseline dopamine transporter availability in the right ventral striatum, anterior‐dorsal striatum, and posterior putamen compared with PD patients without ICD symptoms. No baseline between‐group differences in age and disease stage or duration were found. The ICD symptom severity correlated negatively with baseline dopamine transporter availability in the right ventral and anterior‐dorsal striatum. The results of this preliminary study show that reduced striatal dopamine transporter availability predates the development of ICD symptoms after dopamine replacement therapy and may constitute a neurobiological risk factor related to a lower premorbid dopamine transporter availability or a more pronounced dopamine denervation in PD patients susceptible to ICD. © 2014 International Parkinson and Movement Disorder Society     

Smell identification ability in twin pairs discordant for Parkinson's disease.

Olfactory dysfunction has been proposed to be a sign that may precede the motor features of Parkinson's disease (PD). To determine whether smell identification deficits predict subsequent PD, we studied smell identification ability using the University of Pennsylvania Smell Identification Test (UPSIT) in 62 members of male twin pairs discordant for PD at baseline. Smell identification ability was reduced at baseline in the twins with PD compared to their unaffected brothers (23 vs. 31 of 40; P = 0.001). UPSIT scores were not reduced in the twins without PD when compared to age- and gender-specific normal values. After a mean interval of 7.3 years, 28 unaffected twins were still alive and 19 agreed to a second evaluation. Two had newly developed PD. Neither twin had impaired smell identification at baseline. The average decline in UPSIT percentile scores in these 2 twins was greater than in the 17 twins who did not develop PD (-68% vs. -24%; P = 0.01). In subjects who did not meet Core Assessment Program for Intracerebral Transplantations diagnostic criteria for PD at baseline, the presence of cardinal signs of parkinsonism was not associated with lower baseline UPSIT scores nor with a subsequent decline. Smell identification ability may not be a sensitive indicator of future PD 7 or more years before the development of motor signs, even in a theoretically at-risk population.     

Dopamine agonists and Parkinson's disease

The therapeutic use of dopamine agonists for Parkinson's disease, clinical guidelines for their introduction into antiparkinson regimens, and their range of adverse effects are reviewed. The role played by the dopaminomimetic ergots in elucidating dopamine receptor function, and laboratory methods that identify dopamine agonists, are also examined.     

Heterogeneity of cholinergic denervation in Parkinson's disease without dementia

Parkinson's disease (PD) is a multisystem neurodegenerative disorder. Heterogeneous clinical features may reflect heterogeneous changes in different brain regions. In contrast to the pronounced nigrostriatal denervation characteristic of PD, cholinergic changes are less marked. We investigated cholinergic innervation activity in PD subjects relative to normal subjects. Nondemented PD subjects (n=101, age 65.3±7.2 years) and normal subjects (n=29, age 66.8±10.9 years) underwent clinical assessment and [(11)C]methyl-4-piperidinyl propionate acetylcholinesterase and [(11)C]dihydrotetrabenazine monoaminergic positron emission tomography (PET) imaging. Cholinergic projection changes were heterogeneous for 65 out of 101 PD subjects who had neocortical and thalamic acetylcholinesterase activity within the normal range. The remainder had combined neocortical and thalamic (13/101), isolated neocortical (18/101), or isolated thalamic (5/101) acetylcholinesterase activity below the normal range. The low neocortical acetylcholinesterase activity subgroup had significantly lower global cognitive performance compared with the normal range subgroup (F=7.64, P=0.0069) with an independent effect for nigrostriatal denervation (F=7.60, P=0.0074). The low thalamic acetylcholinesterase activity subgroup did not differ from the normal thalamic acetylcholinesterase activity subgroup in cognitive performance or motor impairments except for a history of falls (P=0.0023). Cholinergic denervation is heterogeneous with reduced neocortical and/or thalamic acetylcholinesterase activity in 36% of nondemented PD subjects with corresponding clinical phenotypic variation. Results also show independent cognitive effects for both cholinergic and dopaminergic system changes in nondemented PD subjects.     

Association between dopamine transporter gene polymorphism and susceptibility to Parkinson's disease in Japan.

We studied a polymorphism in the dopamine transporter (DAT) gene in 236 Japanese patients with Parkinson's disease (PD) and compared the results with 220 controls. The 1215A/G genotype of the DAT gene was significantly different between PD patients and controls, suggesting a possible involvement of DAT in genetic susceptibility to PD.     

Rapid detection of Parkinson's disease by SPECT with altropane: A selective ligand for dopamine transporters

Increasing evidence indicates that dopamine (DA) transporter density declines in Parkinson's disease (PD). 2β-Carbomethoxy-3β-(4-fluorophenyl)-n-(1-iodoprop-1-en-3-yl) nortropane (IACFT, Altropane™) is a cocaine analog with high affinity and selectivity for dopamine transporter (DAT) sites in the striatum. In this study, single photon emission computed tomography (SPECT) with [¹²³I]altropane was used to measure DAT density in seven healthy volunteers (five males, age 37–75, and two females, ages 26 and 39) and eight male patients with Parkinson's disease (age 14–79, Hoehn and Yahr stage: 1.5–3 (n = 5) and 4–5 (n = 3)). Dynamic SPECT images and arterial blood samples were acquired over 1.5–2 hr and plasma radioactivity was analyzed chromatographically to obtain metabolite corrected arterial input functions. Binding potential (BP, B′_max/K_D) for striatal (Str) DAT sites was calculated by two methods using occipital cortex (Occ) as a reference. In the first method, tissue time–activity curves (TAC) and metabolite corrected arterial input functions were analyzed by a linear graphical method developed for reversible receptor ligands. In the second method, the expression (Str_TAC − Occ_TAC) was fitted to a gamma variate function and the maximum divided by Occ_TAC at the same time was used to estimate BP. In five of the PD patients, the SPECT data were compared with the results of PET with [¹⁸F] 6-fluoro DOPA (FD-PET). Plasma analysis indicated that [¹²³I]altropane is rapidly converted to polar metabolites. SPECT images in healthy volunteers showed that [¹²³I]altropane accumulated rapidly and selectively in the striatum and yielded excellent quality images within 1 h after injection. Both methods of analysis revealed a 7.6%/decade reduction in BP and average striatal values (corrected to age 25) were 1.83 ± 0.22 and 2.09 ± 0.20 by methods 1 and 2. In all the PD patients, striatal accumulation was markedly reduced and the pattern of loss was similar to that reported for DA; most profound in the posterior putamen with relative sparing of the caudate nuclei. A comparable pattern was observed with FD-PET. For total striatum, age-corrected BP was significantly (P < 0.001) reduced; 0.83 ± 0.06 (method 1), 0.84 ± 0.07 (method 2). BPs measured by the two methods were remarkably similar and highly correlated r² = 0.88, (P < 0.001). These results indicate that [¹²³I]altropane is an excellent SPECT ligand for imaging the DAT/DA neurons in human brain. The high selectivity and rapid striatal accumulation of the ligand allows for accurate quantitation of DAT sites in less than 2 hr. The results further demonstrate that [¹²³I]altropane is an effective marker for PD. Synapse 29:128–141, 1998. © 1998 Wiley-Liss, Inc.     

Premotor Parkinson's disease: Clinical features and detection strategies

In many areas of medicine, the focus has shifted from treating existing disease to screening and prevention. The technology to screen for Parkinson's disease (PD) already exists. The current challenge is to define the appropriate use of predictive testing for PD. Imaging technologies currently offer the highest degree of accuracy for identifying premotor PD, but they are expensive as screening tools. Efficiency is greatly enhanced by combining imaging with a prescreening test, such as olfactory testing. This two‐step process has the potential to greatly reduce costs while retaining diagnostic accuracy. Ultimately, the role of preclinical detection of PD will be determined by the ability of emerging therapies to influence clinical outcomes. As such, implementation of large‐scale screening strategies awaits the arrival of clearly safe and effective therapies that address the underlying pathogenesis of PD. Current research to evaluate efficient screening methods and to understand the clinical and physiological features of “premotor” PD will lay the foundation for the screening and prevention strategies of the future. © 2008 Movement Disorder Society     

Effect of dopaminergic medication on adenosine 2A receptor availability in patients with Parkinson's disease

ObjectiveTo assess the necessity of withdrawing dopaminergic medication in Parkinson's disease (PD) patients for accurate estimation of adenosine 2A receptor (A_2AR) availability using [¹¹C]TMSX PET imaging. This was accomplished by studying the short-term effect of the cessation of dopaminergic medication on A_2AR availability in non-dyskinetic patients with PD treated with dopaminergic medication.MethodsEight PD patients (age 67.9 ± 5.6 years; 6 men, 2 women) without dyskinesia were enrolled in this study. A_2AR availability was measured using PET imaging with a [7-methyl-¹¹C]-(E)-8-(3,4,5-trimethoxystyryl)-1,3,7-trimethylxanthine ([¹¹C]TMSX) radioligand after a short term cessation of dopaminergic medication (12hrs for levodopa, 24hrs for dopamine agonists and MAO-B inhibitors). Repeated PET imaging was performed while the patients were back ‘on’ their regular dopaminergic medication (median 13 days after first imaging). Conventional MRI was acquired for anatomical reference. Specific binding of [¹¹C]TMSX was quantified as distribution volume ratios (DVR) for caudate, pallidum and putamen using Logan graphical method with clustered gray matter reference region.ResultsNo significant differences were observed for the DVRs in all three striatal regions between ‘on’ and ‘off’ medication states. Strong correlations were also observed between the two states. Statistical equivalence was found in pallidum (TOST equivalence test, p = 0.045) and putamen (TOST equivalence test, p = 0.022), but not in caudate DVR (TOST equivalence test, p = 0.201) between the two medication states.ConclusionsOur results show that dopaminergic medication has no significant short-term effect on the availability of A_2A receptors in putamen and pallidum of patients with PD. However, relatively poor repeatability was demonstrated in the caudate.