Dietary Caffeine and Brain Dopaminergic Function in Parkinson Disease.

OBJECTIVE: This study was undertaken to investigate the effects of dietary caffeine intake on striatal dopamine function and clinical symptoms in Parkinson disease in a cross-sectional and longitudinal setting. METHODS: One hundred sixty-three early Parkinson disease patients and 40 healthy controls were investigated with [123I]FP-CIT single photon emission computed tomography, and striatal dopamine transporter binding was evaluated in association with the level of daily coffee consumption and clinical measures. After a median interval of 6.1 years, 44 patients with various caffeine consumption levels underwent clinical and imaging reexamination including blood caffeine metabolite profiling. RESULTS: Unmedicated early Parkinson disease patients with high coffee consumption had 8.3 to 15.4% lower dopamine transporter binding in all studied striatal regions than low consumers, after accounting for age, sex, and motor symptom severity. Higher caffeine consumption was further associated with a progressive decline in striatal binding over time. No significant effects of caffeine on motor function were observed. Blood analyses demonstrated a positive correlation between caffeine metabolites after recent caffeine intake and dopamine transporter binding in the ipsilateral putamen. INTERPRETATION: Chronic caffeine intake prompts compensatory and cumulative dopamine transporter downregulation, consistent with caffeine's reported risk reduction in Parkinson disease. However, this decline does not manifest in symptom changes. Transiently increased dopamine transporter binding after recent caffeine intake has implications for dopaminergic imaging guidelines. ANN NEUROL 2024;96:262-275.

GPi-DBS-induced brain metabolic activation in cervical dystonia.

BACKGROUND: Deep brain stimulation (DBS) of the globus pallidus interna (GPi) is a highly efficacious treatment for cervical dystonia, but its mechanism of action is not fully understood. Here, we investigate the brain metabolic effects of GPi-DBS in cervical dystonia. METHODS: Eleven patients with GPi-DBS underwent brain 18F-fluorodeoxyglucose positron emission tomography imaging during stimulation on and off. Changes in regional brain glucose metabolism were investigated at the active contact location and across the whole brain. Changes in motor symptom severity were quantified using the Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS), executive function using trail making test (TMT) and parkinsonism using Unified Parkinson's Disease Rating Scale (UPDRS). RESULTS: The mean (SD) best therapeutic response to DBS during the treatment was 81 (22)%. The TWSTRS score was 3.2 (3.9) points lower DBS on compared with off (p=0.02). At the stimulation site, stimulation was associated with increased metabolism, which correlated with DBS stimulation amplitude (r=0.70, p=0.03) but not with changes in motor symptom severity (p>0.9). In the whole brain analysis, stimulation increased metabolism in the GPi, subthalamic nucleus, putamen, primary sensorimotor cortex (PFDR<0.05). Acute improvement in TWSTRS correlated with metabolic activation in the sensorimotor cortex and overall treatment response in the supplementary motor area. Worsening of TMT-B score was associated with activation of the anterior cingulate cortex and parkinsonism with activation in the putamen. CONCLUSIONS: GPi-DBS increases metabolic activity at the stimulation site and sensorimotor network. The clinical benefit and adverse effects are mediated by modulation of specific networks.

Serotonergic and dopaminergic control of impulsivity in gambling disorder.

Gambling disorder (GD) is major public health issue. The disorder is often characterized by elevated impulsivity with evidence from analogous substance use disorders underlining prominent roles of brain monoamines in addiction susceptibility and outcome. Critically, GD allows the study of addiction mechanisms without the confounder of the effects of chronic substances. Here, we assessed the roles of striatal dopamine transporter binding and extrastriatal serotonin transporter binding in GD as a function of impulsivity using [123 I]FP-CIT SPECT imaging in 20 older adults with GD (DSM-5 criteria; mean age 64 years) and 40 non-GD age- and sex-matched controls. We focused on GD in older individuals because there are prominent age-related changes in neurotransmitter function and because there are no reported neuroimaging studies of GD in older adults. Volume-of-interest-based and voxelwise analyses were performed. GD patients scored clearly higher on impulsivity and had higher tracer binding in the ventromedial prefrontal cortex than controls (p < 0.001), likely reflecting serotonin transporter activity. The binding in the medial prefrontal cortex positively correlated with impulsivity over the whole sample (r = 0.62, p < 0.001) as well as separately in GD patients (r = 0.46, p = 0.04) and controls (r = 0.52, p < 0.001). Striatal tracer binding, reflecting dopamine transporter activity was also positively correlated with impulsivity but showed no group differences. These findings highlight the role of prefrontal serotonergic function in GD and impulsivity. They identify cerebral coordinates of a potential target for neuromodulation for both GD and high impulsivity, a core phenotypic dimensional cognitive marker in addictions.

Neurobiological effects of deep brain stimulation: A systematic review of molecular brain imaging studies.

Deep brain stimulation (DBS) is an established treatment for several brain disorders, including Parkinson's disease, essential tremor, dystonia and epilepsy, and an emerging therapeutic tool in many other neurological and psychiatric disorders. The therapeutic efficacy of DBS is dependent on the stimulation target, but its mechanisms of action are still relatively poorly understood. Investigating these mechanisms is challenging, partly because the stimulation devices and electrodes have limited the use of functional MRI in these patients. Molecular brain imaging techniques, such as positron emission tomography (PET) and single photon emission tomography (SPET), offer a unique opportunity to characterize the whole brain effects of DBS. Here, we investigated the direct effects of DBS by systematically reviewing studies performing an `on' vs `off' contrast during PET or SPET imaging. We identified 62 studies (56 PET and 6 SPET studies; 531 subjects). Approximately half of the studies focused on cerebral blood flow or glucose metabolism in patients Parkinson's disease undergoing subthalamic DBS (25 studies, n = 289), therefore Activation Likelihood Estimation analysis was performed on these studies. Across disorders and stimulation targets, DBS was associated with a robust local increase in ligand uptake at the stimulation site and target-specific remote network effects. Subthalamic nucleus stimulation in Parkinson's disease showed a specific pattern of changes in the motor circuit, including increased ligand uptake in the basal ganglia, and decreased ligand uptake in the primary motor cortex, supplementary motor area and cerebellum. However, there was only a handful of studies investigating other brain disorder and stimulation site combinations (1-3 studies each), or specific neurotransmitter systems, preventing definitive conclusions of the detailed molecular effects of the stimulation in these cases.

Diagnostic value of micrographia in Parkinson's disease: a study with [123I]FP-CIT SPECT.

Micrographia is a common symptom of Parkinson's disease (PD), and it may precede other motor symptoms. Despite the high prevalence of micrographia in PD, its neurobiological mechanisms are not known. Given that levodopa may alleviate consistent micrographia and that nondopaminergic essential tremor (ET) is not associated with micrographia, micrographia could possibly be used as an ancillary diagnostic method that reflects nigrostriatal dopamine function. We evaluated the usefulness of micrographia as a simple one-sentence writing test in differentiating PD from ET. A total of 146 PD patients, 42 ET patients and 38 healthy controls provided writing samples and were scanned with brain [123I]FP-CIT dopamine transporter (DAT) SPECT imaging with ROI-based and voxelwise analyses. The diagnostic accuracy of micrographia was evaluated and compared to that of DAT binding. Compared to ET and healthy controls, PD patients showed micrographia (consistent, 25.6% smaller area of handwriting sample in PD compared to ET, p = 0.002, and 27.2% smaller area of handwriting compared to healthy controls, p = 0.004). PD patients showed 133% more severe progressive micrographia compared with ET patients (median b = - 0.14 in PD, b = - 0.06 in ET, p = 0.021). In early unmedicated cognitively normal patients, consistent micrographia showed 71.2% specificity and 87.5% sensitivity in PD versus ET differentiation, but micrographia had no correlation with striatal or extrastriatal [123I]FP-CIT binding in patients with PD. The one-sentence micrographia test shows moderately good accuracy in PD versus ET differentiation. The severity of micrographia has no relationship with DAT binding, suggesting nondopaminergic mechanism of micrographia in PD.ClinicalTrials.gov identifier: NCT02650843 (NMDAT study).

Dopamine transporter binding in symptomatic controls and healthy volunteers: Considerations for neuroimaging trials.

OBJECTIVE: To evaluate possible differences between brain dopamine transporter (DAT) binding in a group of symptomatic parkinsonism patients without dopaminergic degeneration and healthy individuals. BACKGROUND: Dopaminergic neuroimaging studies of Parkinson's disease (PD) have often used control groups formed from symptomatic patients with apparently normal striatal dopamine function. We sought to investigate whether symptomatic patients can be used to represent dopaminergically normal healthy controls. METHODS: Forty healthy elderly individuals were scanned with DAT [123I]FP-CIT SPECT and compared to 69 age- and sex-matched symptomatic patients with nondegenerative conditions (including essential tremor, drug-induced parkinsonism and vascular parkinsonism). An automated region-of-interest based analysis of the caudate nucleus and the anterior/posterior putamen was performed. Specific binding ratios (SBR = [ROI-occ]/occ) were compared between the groups. RESULTS: DAT binding in symptomatic patients was 8.6% higher in the posterior putamen than in healthy controls (p = 0.03). Binding correlated negatively with age in both groups but not with motor symptom severity, cognitive function or depression ratings. CONCLUSIONS: Putaminal DAT binding, as measured with [123I]FP-CIT SPECT, was higher in symptomatic controls than in healthy individuals. The reason for the difference is unclear but can include selection bias when DAT binding is used to aid clinical diagnosis and possible self-selection bias in healthy volunteerism. This effect should be taken into consideration when designing and interpreting neuroimaging trials investigating the dopamine system with [123I]FP-CIT SPECT.

Sex correction improves the accuracy of clinical dopamine transporter imaging.

BACKGROUND: In clinical diagnostic imaging, dopamine transporter (DAT) SPECT scans are commonly evaluated using automated semiquantitative analysis software. Age correction is routinely implemented, but usually no sex correction of DAT binding is performed. Since there are sex differences in presynaptic dopaminergic function, we investigated the effect of DAT sex correction in a sample of healthy volunteers who underwent brain [123I]-FP-CIT SPECT. METHODS: Forty healthy elderly individuals (21 men and 19 women) underwent brain [123I]-FP-CIT SPECT, and each subject was examined clinically for motor and non-motor parkinsonian symptoms and signs. Regional specific DAT binding ratios (SBR = [ROI-occ]/occ) were calculated using age correction, and the results were compared to those in normal databases with and without sex correction. The level of regional abnormality was set at 2 standard deviations below the mean values of the reference databases. RESULTS: In the analysis without sex correction, compared to the mean ratio of the reference database, ten healthy individuals (8 men and 2 women) had abnormally low DAT binding ratios, and four individuals (3 men and 1 woman) had borderline low DAT binding ratios in at least one striatal region. When sex correction was implemented, the ratio of one individual was abnormal, and the ratio of one individual was borderline (both males). There were no clinically significant differences in motor or non-motor symptoms between healthy volunteers with abnormal and normal binding. CONCLUSIONS: A considerable number of elderly healthy male subjects can be interpreted to be dopaminergically abnormal if no sex correction of DAT binding is performed. Sex differences in striatal dopaminergic function should be taken into account when DAT imaging is used to assist clinical diagnostics in patients with suspected neurological disorders.

Diagnostic accuracy of glabellar tap sign for Parkinson's disease.

Glabellar tap or reflex (GR) is an old bedside clinical test used in the diagnostics of Parkinson's disease (PD), but its diagnostic value is unclear. This study examines the diagnostic validity and reliability of GR in PD in relation to brain dopaminergic activity. GR was performed on 161 patients with PD, 47 patients with essential tremor (ET) and 40 healthy controls immediately prior to dopamine transporter (DAT) [123I]FP-CIT SPECT scanning. The binding ratios were investigated with consideration of the GR result (normal/abnormal). In addition, the consistency of the GR was investigated with 89 patients after a mean follow-up of 2.2 years. PD and ET patients had higher GR scores than healthy controls (p < 0.001), but there was no difference in GR between PD and ET patients (p = 0.09). There were no differences in the ratio of abnormal to normal GRs between the PD and ET groups (73% vs. 64% abnormal, respectively, p = 0.13) or in DAT binding between PD patients with abnormal and normal GRs (p > 0.36). Over follow-up, the GR changed from abnormal to normal in 20% of PD patients despite the presence of clinically typical disease. The sensitivity and specificity of GR for differentiating PD from ET were 78.3% and 36.2%, respectively. Although GR has been used by clinicians in the diagnostics of PD, it does not separate PD from ET. It also shows considerable inconsistency over time, and abnormal GR has no relationship with dopamine loss. Its usefulness should be tested for other clinical diagnostic purposes.

Reappearance of Symptoms after GPi-DBS Discontinuation in Cervical Dystonia.

BACKGROUND: Deep brain stimulation of the globus pallidus interna (GPi-DBS) is a highly efficacious treatment for cervical dystonia. Typically, the treatment response is delayed, appearing and increasing even months after implantation. However, it is not known how fast the symptoms reappear and whether there is a long-term therapeutic effect after the stimulation is discontinued. OBJECTIVES: To study symptom reappearance after switching GPi-DBS off in cervical dystonia. METHODS: Twelve patients with bilateral GPi-DBS were included in the study. The Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS) was evaluated during the study with DBS stimulation on, after switching the stimulation off and 2 days after the stimulation was switched off. Presurgical symptom severity and best postsurgical response were extracted from the hospital records. RESULTS: At the time of the investigation, GPi-DBS was associated with 67 (SD 39)% symptom improvement of presurgical symptoms severity (P = 0.001). Symptom improvement decreased to 27 (53)% (P = 0.046) (n = 12) acutely after switching the stimulation off and was further reduced to 4 (56)% 2 days after discontinuation (P = 0.01) (n = 11), reaching the presurgical level (P = 0.42). In descriptive analyses, older age was associated with faster worsening of symptoms (P < 0.05). Presurgical symptoms severity, stimulation parameters or magnitude of treatment response did not predict symptom worsening. All but one patient tolerated 2 days DBS switched off. CONCLUSIONS: The results provide novel information about the time frame and severity of symptom worsening after discontinuing GPi-DBS in cervical dystonia. Symptoms partially reappear immediately after discontinuing GPi-DBS and full presurgical symptom severity is reached within 2 days.

Bupropion Causes Misdiagnosis in Brain Dopamine Transporter Imaging for Parkinsonism.

OBJECTIVE: The objective of this study was to report long-lasting effects of bupropion on brain dopamine transporter (DAT) in a patient with depression and parkinsonism. METHODS: The patient was a 52-year old man who had been treated with 150 mg/d of bupropion for depression. The patient developed cognitive problems, bradykinesia, and reduced stride length for which he was scanned with [I]FP-CIT single photon emission computed tomography after the recommended 1-week discontinuation of bupropion. Levodopa treatment trial was initiated without a response. Eleven months later, the patient was scanned for a second time after a 1-month stoppage of bupropion. RESULTS: The first scan was abnormal with left putamen specific binding ratio of 1.99 (SDs from the reference value mean, -2.40), right putamen of 2.27 (SD, -1.84), left caudate of 2.33 (SD, -2.26), and right caudate of 2.29 (SD, -2.18). The second scan (after 1-month discontinuation) was normal, and specific binding ratios had increased from 5.2% to 31.7% in all striatal regions as compared with the first scan. Brain magnetic resonance imaging and [F]fluorodeoxyglucose positron emission tomography imaging were normal, and there was no levodopa response or other features supporting neurodegenerative parkinsonism. CONCLUSIONS: Bupropion has previously generally been discontinued 1 week prior DAT imaging, which meets the recommended, albeit arbitrary, time interval of 5 plasma clearance half-lives before the scan. One-week discontinuation of bupropion before DAT imaging may be insufficiently short. Our case shows that longer medication washout and rescan may be needed when there is contradiction between the imaging result and clinical outcome in patients with medications affecting DAT binding.

No link between striatal dopaminergic axons and dopamine transporter imaging in Parkinson's disease.

BACKGROUND: Brain dopamine transporter binding has been considered a possible biomarker for nigrostriatal degeneration in PD. OBJECTIVE: To investigate whether dopamine transporter binding is associated with the number of dopaminergic neurites in the putamen. METHODS: Tyrosine hydroxylase-positive nerve fibers were counted from postmortem putamen sections taken from 14 parkinsonism patients who had been scanned with dopamine transporter single-photon emission computed tomography antemortem. Fiber counts were correlated with putamen dopamine transporter binding and SN neuron counts. RESULTS: The putamen dopamine transporter specific binding ratio did not correlate with the putamen tyrosine hydroxylase-positive axon counts (r = 0.00; P = 1.0; PD patients: r = 0.07; P = 0.86). The nigra neuron counts had a positive correlation with the putamen tyrosine hydroxylase-positive axon counts. CONCLUSIONS: Striatal dopamine transporter imaging does not associate with axonal nor somal loss of the nigrostriatal neurons in PD. It may reflect dopaminergic activity rather than number of surviving neurons or their striatal projection axons. © 2019 International Parkinson and Movement Disorder Society.