Dopamine Storage Capacity Research Articles

Imaging progressive peripheral and central dysfunction in isolated REM sleep behaviour disorder after 3 years of follow-up

IntroductionMost patients with isolated rapid eye movement sleep behaviour disorder (iRBD) convert to Parkinson's disease (PD), dementia with Lewy bodies, or multiple system atrophy within 15 years of diagnosis. Furthermore, iRBD patients develop non-motor symptoms similar to those of manifest PD patients and display dysfunction of the sympathetic and parasympathetic nervous system, comparable to that seen in PD. However, progression rates of autonomic dysfunction in iRBD have not been studied with objective measures in detail, which is the aim of this study. MethodsTwenty-two iRBD patients were included at baseline and 14 participated in follow-up after 3 years. Colonic transit time (CTT) was examined using radio opaque markers, colonic volume was defined on abdominal computed tomography (CT) scans, Iodine-123-metaiodobenzylguanidine ([123I]MIBG) scintigraphy was performed to assess cardiac sympathetic innervation, and 3,4-dihydroxy-6-(18F) fluoro-l-phenylalanine ([18F]FDOPA) positron emission tomography (PET) scan determined nigrostriatal dopamine storage capacity. All examinations were performed at baseline and after 3 years. ResultsiRBD patients displayed increased CTT (p = 0.001) and colonic volume (p = 0.01) at follow-up compared to baseline. Furthermore, [123I]MIBG uptake and [18F]FDOPA uptake showed progressive reductions at follow-up (p = 0.02 and p = 0.002, respectively). No correlations were seen between changes in intestinal or cardiac measurements and dopaminergic function. ConclusionUsing objective markers, the present study documented that intestinal dysfunction and cardiac sympathetic degeneration worsen in the majority of iRBD patients over a 3-year period. The absent correlation between these markers and nigrostriatal dopaminergic dysfunction suggests that progressive gastrointestinal and cardiac dysfunction in iRBD is caused mainly by non-dopaminergic mechanisms.

Altered sensorimotor cortex noradrenergic function in idiopathic REM sleep behaviour disorder – A PET study

IntroductionNoradrenergic denervation is thought to aggravate motor dysfunction in Parkinson's disease (PD). In a previous PET study with the norepinephrine transporter (NART) ligand 11C-MeNER, we detected reduced NART binding in primary sensorimotor cortex (M1S1) of PD patients. Idiopathic rapid-eye-movement sleep behaviour disorder (iRBD) is a phenotype of prodromal PD. Using 11C-MeNER PET, we investigated whether iRBD patients showed similar NART binding reductions in M1S1 cortex as PD patients. Additionally, we investigated whether 11C-MeNER binding and loss of nigrostriatal dopamine storage capacity measured with 18F-DOPA PET were correlated. Methods17 iRBD patients, 16 PD patients with (PDRBD+) and 14 without RBD (PDRBD−), and 25 control subjects underwent 11C-MeNER PET. iRBD patients also had 18F-DOPA PET. Volume-of-interest analyses and voxel-level statistical parametric mapping were performed. ResultsPartial-volume corrected 11C-MeNER binding potential (BPND) values in M1S1 differed across the groups (P = 0.022) with the iRBD and PDRBD+ groups showing significant reductions (controls vs. iRBD P = 0.007; control vs. PDRBD+P = 0.008). Voxel-wise comparisons confirmed reductions of M1S1 11C-MeNER binding in PD and iRBD patients. Significant correlation was seen between putaminal 18F-DOPA uptake and thalamic 11C-MeNER binding in iRBD patients (r2 = 0.343, P = 0.013). ConclusionsThis study found altered noradrenergic neurotransmission in the M1S1 cortex of iRBD patients. The observed reduction of M1S1 11C-MeNER binding in iRBD may represent noradrenergic terminal degeneration or physiological down-regulation of NARTs in this prodromal phenotype of PD. The correlation between thalamic 11C-MeNER binding and putaminal 18F-DOPA binding suggests that these neurotransmitter systems degenerate in parallel in the iRBD phenotype of prodromal PD.

In-vivo staging of pathology in REM sleep behaviour disorder: a multimodality imaging case-control study

Accumulating evidence suggests that α-synuclein aggregates-a defining pathology of Parkinson's disease-display cell-to-cell transmission. α-synuclein aggregation is hypothesised to start in autonomic nerve terminals years before the appearance of motor symptoms, and subsequently spread via autonomic nerves to the spinal cord and brainstem. To assess this hypothesis, we investigated sympathetic, parasympathetic, noradrenergic, and dopaminergic innervation in patients with idiopathic rapid eye movement (REM) sleep behaviour disorder, a prodromal phenotype of Parkinson's disease. In this prospective, case-control study, we recruited patients with idiopathic REM sleep behaviour disorder, confirmed by polysomnography, without clinical signs of parkinsonism or dementia, via advertisement and through sleep clinics in Denmark. We used 11C-donepezil PET and CT to assess cholinergic (parasympathetic) gut innervation, 123I-metaiodobenzylguanidine (MIBG) scintigraphy to measure cardiac sympathetic innervation, neuromelanin-sensitive MRI to measure integrity of pigmented neurons of the locus coeruleus, 11C-methylreboxetine (MeNER) PET to assess noradrenergic nerve terminals originating in the locus coeruleus, and 18F-dihydroxyphenylalanine (DOPA) PET to assess nigrostriatal dopamine storage capacity. For each imaging modality, we compared patients with idiopathic REM sleep behaviour disorder with previously published reference data of controls without neurological disorders or cognitive impairment and with symptomatic patients with Parkinson's disease. We assessed imaging data using one-way ANOVA corrected for multiple comparisons. Between June 3, 2016, and Dec 19, 2017, we recruited 22 consecutive patients with idiopathic REM sleep behaviour disorder to the study. Compared with controls, patients with idiopathic REM sleep behaviour disorder had decreased colonic 11C-donepezil uptake (-0·322, 95% CI -0·112 to -0·531; p=0·0020), 123I-MIBG heart:mediastinum ratio (-0·508, -0·353 to -0·664; p<0·0001), neuromelanin-sensitive MRI locus coeruleus:pons ratio (-0·059, -0·019 to -0·099; p=0·0028), and putaminal 18F-DOPA uptake (Ki; -0·0023, -0·0009 to -0·0037; p=0·0013). No between-group differences were detected between idiopathic REM sleep behaviour disorder and Parkinson's disease groups with respect to 11C-donepezil (p=0·39), 123I-MIBG (p>0·99), neuromelanin-sensitive MRI (p=0·96), and 11C-MeNER (p=0·56). By contrast, 15 (71%) of 21 patients with idiopathic REM sleep behaviour disorder had 18F-DOPA Ki values within normal limits, whereas all patients with Parkinson's disease had significantly decreased 18F-DOPA Ki values when compared with patients with idiopathic REM sleep behaviour disorder (p<0·0001). Patients with idiopathic REM sleep behaviour disorder had fully developed pathology in the peripheral autonomic nervous system and the locus coeruleus, equal to that in diagnosed Parkinson's disease. These patients also showed noradrenergic thalamic denervation, but most had normal putaminal dopaminergic storage capacity. This caudorostral gradient of dysfunction supports the hypothesis that α-synuclein pathology in Parkinson's disease initially targets peripheral autonomic nerves and then spreads rostrally to the brainstem. Lundbeck Foundation, Jascha Foundation, and the Swiss National Foundation.

Effects of Smoking Cessation on Presynaptic Dopamine Function of Addicted Male Smokers

BackgroundThere is evidence of abnormal cerebral dopamine transmission in nicotine-dependent smokers, but it is unclear whether dopaminergic abnormalities are due to acute nicotine abuse or whether they persist with abstinence. We addressed this question by conducting longitudinal positron emission tomography (PET) examination of smokers before and after 3 months of abstinence. MethodsWe obtained baseline 6-[18F]fluoro-L-DOPA (FDOPA)-PET scans in 15 nonsmokers and 30 nicotine-dependent smokers, who either smoked as per their usual habit or were in acute withdrawal. All smokers then underwent cessation treatment, and successful abstainers were re-examined by FDOPA-PET after 3 months of abstinence (n = 15). Uptake of FDOPA was analyzed using a steady-state model yielding estimates of the dopamine synthesis capacity (K); the turnover of tracer dopamine formed in living brain (kloss); and the tracer distribution volume (Vd), which is an index of dopamine storage capacity. ResultsCompared with nonsmokers, K was 15% to 20% lower in the caudate nuclei of consuming smokers. Intraindividual comparisons of consumption and long-term abstinence revealed significant increases in K in the right dorsal and left ventral caudate nuclei. Relative to acute withdrawal, Vd significantly decreased in the right ventral and dorsal caudate after prolonged abstinence. Severity of nicotine dependence significantly correlated with dopamine synthesis capacity and dopamine turnover in the bilateral ventral putamen of consuming smokers. ConclusionsThe results suggest a lower dopamine synthesis capacity in nicotine-dependent smokers that appears to normalize with abstinence. Further investigations are needed to clarify the role of dopamine in nicotine addiction to help develop smoking prevention and cessation treatments.

The Impact of Dopamine on Aggression: An [18F]-FDOPA PET Study in Healthy Males

Cerebral dopamine (DA) transmission is thought to be an important modulator for the development and occurrence of aggressive behavior. However, the link between aggression and DA transmission in humans has not been investigated using molecular imaging and standardized behavioral tasks. We investigated aggression as a function of DA transmission in a group of (N = 21) healthy male volunteers undergoing 6-[18F]-fluoro-L-DOPA (FDOPA)-positron emission tomography (PET) and a modified version of the Point Subtraction Aggression Paradigm (PSAP). This task measures aggressive behavior during a monetary reward-related paradigm, where a putative adversary habitually tries to cheat. The participant can react in three ways (i.e., money substraction of the putative opponent [aggressive punishment], pressing a defense button, or continuing his money-making behavior). FDOPA-PET was analyzed using a steady-state model yielding estimates of the DA-synthesis capacity (K), the turnover of tracer DA formed in living brain (kloss), and the tracer distribution volume (Vd), which is an index of DA storage capacity. Significant negative correlations between PSAP aggressive responses and the DA-synthesis capacity were present in several regions, most prominently in the midbrain (r = -0.640; p = 0.002). Lower degrees of aggressive responses were associated with higher DA storage capacity in the striatum and midbrain. Additionally, there was a significant positive correlation between the investment into monetary incentive responses on the PSAP and DA-synthesis capacity, notably in the midbrain (r = +0.618, p = 0.003). The results suggest that individuals with low DA transmission capacity are more vulnerable to reactive/impulsive aggression in response to provocation.

Effects of anticholinergic challenge on psychopathology and cognition in drug-free patients with schizophrenia and healthy volunteers

Several aspects of the neurobiology of schizophrenia, especially the background of the negative symptoms and cognitive deficits, are still insufficiently understood. Tandon and Greden (1989) postulated a central role of dopaminergic/cholinergic imbalance in pathophysiology of schizophrenia. The purpose of our study was to investigate the effects of an anticholinergic challenge (performed by application of biperiden, a central selective M1-muscarinic receptor antagonist) on psychopathology, cognition and attention in 12 unmedicated patients with schizophrenia and 12 healthy controls. The anticholinergic challenge resulted in a considerable increase in PANSS scores and in cognitive impairments, which were significantly more pronounced in patients than in healthy volunteers. Thereby, the PANSS total score increase showed a significant negative correlation with age in patients but not in controls. These results could be a hint to increased dopaminergic transmission after anticholinergic challenge. The age-related diminished reaction in patients could be a consequence of the age-dependent decline of steady state dopamine storage capacity. The neurocognitive impairments caused by a selective M1 receptor antagonismus are in concordance with the previously reported negative impact of anticholinergics on cognition. The more pronounced impairments in patients compared to the controls speak on behalf the initially assumption of dopaminergic/cholinergic imbalance in schizophrenia. This study was supported by DFG

Increased Turnover of Dopamine in Caudate Nucleus of Detoxified Alcoholic Patients

A previous study of the DOPA decarboxylase substrate 6-[18F]fluoro-L-DOPA (FDOPA) with positron emission tomography (PET) detected no difference of the net blood-brain transfer rate (Kinapp) between detoxified alcoholic patients and healthy controls. Instead, the study revealed an inverse correlation between Kinapp in left ventral striatum and alcohol craving scores. To resolve the influx and efflux phases of radiolabeled molecules, we independently estimated the unidirectional blood-brain FDOPA clearance rate (K) and the washout rate of [18F]fluorodopamine and its deaminated metabolites (k loss), and we also calculated the total distribution volume of decarboxylated metabolites and unmetabolized FDOPA as a steady-state index of the dopamine storage capacity (Vd) in brain. The craving scores in the 12 alcoholics correlated positively with the rate of loss (kloss) in the left ventral striatum. We conclude that craving is most pronounced in the individuals with relatively rapid dopamine turnover in the left ventral striatum. The blood-brain clearance rate (K), corrected for subsequent loss of radiolabeled molecules from brain, was completely normal throughout the brain of the alcoholics, in whom the volume of distribution (Vd) was found to be significantly lower in the left caudate nucleus. The magnitude of Vd in the left caudate head was reduced by 43% relative to the 16 controls, consistent with a 58% increase of kloss. We interpret the findings as indicating that a trait for rapid dopamine turnover in the ventral striatum subserves craving and reward-dependence, leading to an acquired state of increased dopamine turnover in the dorsal striatum of detoxified alcoholic patients.

Correlation of dopaminergic terminal dysfunction and microstructural abnormalities of the basal ganglia and the olfactory tract in Parkinson’s disease

Signal abnormalities of the substantia nigra and the olfactory tract detected either by diffusion tensor imaging, including measurements of mean diffusivity, a parameter of brain tissue integrity, and fractional anisotropy, a parameter of neuronal fibre integrity, or transcranial sonography, were recently reported in the early stages of Parkinson's disease. In this study, changes in the nigral and olfactory diffusion tensor signal, as well as nigral echogenicity, were correlated with clinical scales of motor disability, odour function and putaminal dopamine storage capacity measured with 6-[(18)F] fluorolevodopa positron emission tomography in early and advanced stages of Parkinson's disease. Diffusion tensor imaging, transcranial sonography and positron emission tomography were performed on 16 patients with Parkinson's disease (mean disease duration 3.7 ± 3.7 years, Hoehn and Yahr stage 1 to 4) and 14 age-matched healthy control subjects. Odour function was measured by the standardized Sniffin' Sticks Test. Mean putaminal 6-[(18)F] fluorolevodopa influx constant, mean nigral echogenicity, mean diffusivity and fractional anisotropy values of the substantia nigra and the olfactory tract were identified by region of interest analysis. When compared with the healthy control group, the Parkinson's disease group showed significant signal changes in the caudate and putamen by 6-[(18)F] fluorolevodopa positron emission tomography, in the substantia nigra by transcranial sonography, mean diffusivity and fractional anisotropy (P < 0.001, P < 0.01, P < 0.05, respectively) and in the olfactory tract by mean diffusivity (P < 0.05). Regional mean diffusivity values of the substantia nigra and the olfactory tract correlated significantly with putaminal 6-[(18)F] fluorolevodopa uptake (r = -0.52, P < 0.05 and r = -0.71, P < 0.01). Significant correlations were also found between nigral mean diffusivity values and the Unified Parkinson's Disease Rating Scale motor score (r = -0.48, P < 0.01) and between mean putaminal 6-[(18)F] fluorolevodopa uptake and the total odour score (r = 0.58; P < 0.05) as well as the Unified Parkinson's Disease Rating Scale motor score (r = -0.53, P < 0.05). This study reports a significant association between increased mean diffusivity signal and decreased 6-[(18)F] fluorolevodopa uptake, indicating that microstructural degradation of the substantia nigra and the olfactory tract parallels progression of putaminal dopaminergic dysfunction in Parkinson's disease. Since increases in nigral mean diffusivity signal also correlated with motor dysfunction, diffusion tensor imaging may serve as a surrogate marker for disease progression in future studies of putative disease modifying therapies.

Dopamine-Modulated Aversive Emotion Processing Fails in Alcohol-Dependent Patients

Negative mood states after alcohol detoxification may enhance the relapse risk. As recently shown in healthy volunteers, dopamine storage capacity (V d) in the left amygdala was positively correlated with functional activation in the left amygdala and anterior cingulate cortex (ACC) during an emotional task; high functional connectivity between the amygdala and the ACC, a region important for emotion regulation, was associated with low trait anxiety. Based on these findings, we now tested whether detoxified alcohol-dependent patients have a disrupted modulation of the anterior cingulate cortex activation in response to aversive stimuli by amygdala dopamine. Furthermore, we asked whether disrupted functional coupling between amygdala and ACC during aversive processing is related to trait anxiety.We used combined 6-[18F]-fluoro-l-DOPA positron emission tomography (PET), functional magnetic resonance imaging (fMRI) and Spielberger's state-trait anxiety questionnaire (STAI) in 11 male detoxified alcohol-dependent patients compared to 13 matched healthy controls.Unlike healthy controls, patients showed no significant correlation between our PET metric for dopamine storage capacity (FDOPA V d), in left amygdala and activation in left ACC. Moreover, the functional connectivity between amygdala and ACC during processing of aversive emotional stimuli was reduced in patients. Voxel-based morphometry did not reveal any discernible group differences in amygdala volume.These results suggest that dopamine-modulated corticolimbic circuit function is important for responding to emotional information such that apparent functional deficits in this neuromodulatory circuitry may contribute to trait anxiety in alcohol-dependent patients.

Bad News for Neuroprotective Therapies in PD?

While the etiopathogenesis of Parkinson’s disease (PD) continues to fuel intense debate [1], there is little doubt that the motor features of PD are caused by the degeneration of nigrostriatal dopamine (DA) neurons [2]. Clinical symptoms have been estimated to appear when at least 50% nigral DA neurons and 70% putaminal DA tissue contents are lost [3, 4]. Dopaminergic imaging suggests that at least 30% DA storage capacity (18F-dopa PET) and 50% of putamen DA transporters (DAT SPECT) have been lost by the onset of contralateral limb bradykinesia and rigidity [5–7]. Parkinsonian motor features are highly responsive to DA replacement therapy, which provides a stable symptomatic improvement for approximately 4–7 years. After this “honeymoon” period, the patients’ motor response to levodopa starts to fluctuate, and other complications, such as involuntary movements (dyskinesias), start to appear (reviewed in [8, 9]. The clinical history outlined above has assumed a continuing, gradual degeneration of nigrostriatal DA projections causing a progressive loss of DA terminals and DA storage capacity in the striatum (reviewed in [10]. The steady progression of this process is, however, challenged by a pathological investigation by Kordower and coworkers, published in the August issue of Brain [11]. In this study, putaminal and nigral sections from 28 subjects affected by idiopathic PD and 9 age-matched controls were immunohistochemically stained for the

Fatigue in Parkinson's disease is linked to striatal and limbic serotonergic dysfunction

Disabling fatigue is a symptom in a number of neurological diseases, including multiple sclerosis, stroke and Parkinson's disease. We used ¹⁸F-dopa and ¹¹C-DASB [N,N-dimethyl-2-(2-amino-4-cyanophenylthio) benzylamine] positron emission tomography, markers of dopamine storage capacity and serotonin transporter availability, to investigate whether fatigue in Parkinson's disease is associated with dopaminergic and serotonergic dysfunction in basal ganglia and limbic circuits. Ten patients with Parkinson's disease and fatigue and 10 patients without fatigue had a ¹⁸F-dopa scan. Seven patients with and eight patients without fatigue also had a ¹¹C-DASB scan. The two groups were matched for age, disease duration and severity and daily intake of levodopa equivalent units. None had a history of depression or sleep disturbance. Using a region of interest analytical approach, we found that patients with fatigue had significantly lower serotonin transporter binding than patients without fatigue in the caudate, putamen, ventral striatum and thalamus. Striatal ¹⁸F-dopa uptake was similar in the fatigued and non-fatigued groups. Voxel-based analysis localized further relative serotonin transporter binding reductions in the cingulate and amygdala of the fatigue group, and ¹⁸F-dopa uptake reductions in the caudate and insula. We conclude that fatigue in Parkinson's disease is associated with reduced serotonergic function in the basal ganglia and limbic structures. Insular dopaminergic dysfunction could also play a role. These findings imply that strategies to increase brain level of serotonin would be a rational approach for relieving fatigue symptoms in Parkinson's disease and may also be relevant to alleviating fatigue in other clinical conditions.

Functional enhancement and protection of dopaminergic terminals by RAB3B overexpression

In Parkinson's disease (PD), dopaminergic (DA) neurons in the substantia nigra (SN, A9) are particularly vulnerable, compared to adjacent DA neurons within the ventral tegmental area (VTA, A10). Here, we show that in rat and human, one RAB3 isoform, RAB3B, has higher expression levels in A10 compared to A9 neurons. RAB3 is a monomeric GTPase protein that is highly enriched in synaptic vesicles and is involved in synaptic vesicle trafficking and synaptic transmission, disturbances of which have been implicated in several neurodegenerative diseases, including PD. These findings prompted us to further investigate the biology and neuroprotective capacity of RAB3B both in vitro and in vivo. RAB3B overexpression in human dopaminergic BE (2)-M17 cells increased neurotransmitter content, [(3)H] dopamine uptake, and levels of presynaptic proteins. AAV-mediated RAB3B overexpression in A9 DA neurons of the rat SN increased striatal dopamine content, number and size of synaptic vesicles, and levels of the presynaptic proteins, confirming in vitro findings. Measurement of extracellular DOPAC, a dopamine metabolite, following l-DOPA injection supported a role for RAB3B in enhancing the dopamine storage capacity of synaptic terminals. RAB3B overexpression in BE (2)-M17 cells was protective against toxins that simulate aspects of PD in vitro, including an oxidative stressor 6-hydroxydopamine (6-OHDA) and a proteasome inhibitor MG-132. Furthermore, RAB3B overexpression in rat SN both protected A9 DA neurons and resulted in behavioral improvement in a 6-OHDA retrograde lesion model of PD. These results suggest that RAB3B improves dopamine handling and storage capacity at presynaptic terminals, and confers protection to vulnerable DA neurons.

Non-motor extranigral signs and symptoms in Parkinson's disease

Clinical symptoms in Parkinson's disease (PD) comprise both motor and non-motor symptoms. In this disease, synucleinopathic-induced, nigral dopamine deficiency-related dysfunction of the basal ganglia is held responsible for the characteristic levodopa-responsive motor signs and symptoms (bradykinesia, hypokinesia, rigidity), known as parkinsonism and essential for clinical diagnosis in PD, as well as subtle motivational and cognitive dysfunctions. Some motor symptoms, such as tremor and postural instability, and most non-motor symptoms, however, are not fully levodopa-responsive, and suggested to manifest extranigral pathology. These symptoms include autonomic, sleep, sensory and neuropsychiatric symptoms, which in some cases may precede the first signs of motor parkinsonism, closely correlating with the progression of Lewy body pathology in PD. The recognition and treatment of these mostly under-recognized and under-treated symptoms is important, as these symptoms might have more impact on the quality of life in PD patients as compared to motor parkinsonism. On top of this, recognition of these manifestations in the prodromal phase of motor PD is critical to early diagnosis and treatment, as disease-modifying drugs, once identified, should be initiated as soon as possible, preferably in this premotor phase of the disease. On top of this, (non)motor extranigral symptoms in PD might also be of iatrogenic origin, whether directly as indirectly. During conventional, oral, dopaminomimetic treatment, the progressive loss of striatal dopaminergic nerve endings with the loss of cerebral dopamine storage capacity, renders the cerebral dopamine level fully dependent of the plasma levodopa levels, thus changing dopaminergic receptor stimulation from continuous to a more pulsatile pattern. Supposedly due to this process, neuroplastic changes in (sub)cortical dopaminergic pathways might cause therapeutic response fluctuations: motor and nonmotor fluctuations with anxiety- and panic-attacks and/or mood swings, dyskinesias and punding. Finally, dopaminomimetic pharmacotherapy may also induce extranigral non-motor drug-related direct adverse effects, such as impulse control disorders. In this article, non-motor signs and symptoms of extranigral PD-related pathology will be discussed, as well as the (suggested) criteria for diagnosis and treatment. Of course, also the recognition of the signs and symptoms of the prodromal (premotor) phase, suggestive for the presence of the PD, will be discussed. Iatrogenic non-motor symptoms, though, will not be further discussed.

The Intricacies of Dopamine Neuron Modulation

The Intricacies of Dopamine Neuron Modulation

Dopamine in amygdala gates limbic processing of aversive stimuli in humans

Dopamine is released under stress and modulates processing of aversive stimuli. We found that dopamine storage capacity in human amygdala, measured with 6-[(18)F]fluoro-L-DOPA positron emission tomography, was positively correlated with functional magnetic resonance imaging blood oxygen level-dependent signal changes in amygdala and dorsal anterior cingulate cortex that were evoked by aversive stimuli. Furthermore, functional connectivity between these two regions was inversely related to trait anxiety. Our results suggest that individual dopamine storage capacity in amygdala subserves modulation of emotional processing in amygdala and dorsal cingulate, thereby contributing to individual differences in anxious temperament.

Age-dependent decline of steady state dopamine storage capacity of human brain: An FDOPA PET study

Conventional indices of the utilization of FDOPA in living human brain have not consistently revealed important declines in dopamine function with normal aging. However, most methods of kinetic analysis have assumed irreversible trapping of decarboxylated FDOPA metabolites in brain, an assumption that is violated even in PET recordings of short duration. Therefore, we have developed methods for the calculation of steady-state storage of FDOPA together with its decarboxylated metabolites ( V d, ml g −1), based upon improved kinetic analysis of 120-min emission recordings. In a group of 28 normal male subjects, of age ranging from 23 to 73 years, the magnitude of V d in the striatum and in extrastriatal regions declined by approximately 10% with each decade. The utilization of FDOPA was also calculated by several conventional methods assuming irreversible trapping, i.e. the net blood brain clearance ( K in app , ml g −1 min −1), the DOPA decarboxylase activity relative to a reference tissue input ( k 3 S , min −1), and relative to the arterial input ( k 3 D , min −1). None of these methods revealed an age-related decline in FDOPA utilization in the extended striatum, although the magnitude of K in app did decline in cerebral cortex. Thus, the capacity to synthesize [ 18F]fluorodopamine remained largely intact in striatum of the elderly subjects, but in the presence of a substantially increased rate of washout ( k loss), which was evident in all brain regions examined. Consequently, the magnitude of V d declined with healthy aging, possibly reflecting impaired vesicular storage capacity, resulting in enhanced exposure of cytosolic [ 18F]fluorodopamine to monoamine oxidase.

Sex Differences in K+‐Evoked Striatal Dopamine Output from Superfused Striatal Tissue Fragments of Reserpine‐Treated CD‐1 Mice

Reserpine inhibits vesicular monoamine transporter-2 (VMAT-2) function and thereby impairs vesicular dopamine (DA) storage within nerve terminals. The present report compared the effects of reserpine treatment upon the striatal dopaminergic system in male and female mice as a means to assess potential sex differences in VMAT-2/DA storage function. After treatment with reserpine, male mice showed significantly greater striatal DA concentrations and K+ -evoked DA output from the striatum compared to females. By contrast, no statistically significant sex differences were observed in methamphetamine-evoked DA output in reserpine-treated mice. These results demonstrate a clear sex difference in the striatal dopaminergic responses to reserpine and suggest that females possess a more active VMAT-2/DA storage capacity, as indicated by the greater degree of deficits observed when VMAT-2/DA storage function is inhibited by reserpine. Such findings have important implications for understanding some of the bases for sex differences in neurotoxicity and neurodegeneration of the nigrostriatal dopaminergic system.

Management of motor complications in advanced Parkinson's disease

After several years of smooth and stable response to levodopa, many patients develop motor fluctuations manifested by "on" and "off" phases. There are various subtypes of motor fluctuations that have different underlying mechanisms and therapeutical strategies. The "wearing off" phenomenon may be mainly due to the loss of stratial dopamine storage capacity and short levodopa half-life. The "delayed on" and "no-on" phenomena may be due to impaired absorption of oral levodopa. Management include various combined approaches, such as administration of small multiple daily doses of levodopa, controlled release, dispersible and soluble levodopa formulations, oral dermal- patch and subcutaneous dopamine agonists, MAO-B and COMT inhibitors, and surgical approaches, i.e., subthalamic deep brain stimulation. Future strategies may include gene therapy (e.g., intrastriatal GDNF) or transplantation of stem cells that can either produce and release dopamine or generate trophical factors.

Dopamine Storage Capacity in Caudate and Putamen of Patients with Early Parkinson's Disease: Correlation with Asymmetry of Motor Symptoms

Conventional graphical analysis of positron emission tomography (PET) recordings of the cerebral uptake of the DOPA decarboxylase substrate [(18)F]fluorodopa (FDOPA) assumes irreversible trapping of [(18)F]fluorodopamine formed in the brain. However, 4-h long PET recordings allow the estimation of a rate constant for elimination of [(18)F]fluorodopamine from the brain (k(loss)), from which can be calculated an effective distribution volume (EDV(1)), which is an index of [(18)F]fluorodopamine storage capacity. We earlier developed a method employing 2-h long FDOPA recordings for the estimation of k(loss) and EDV, here defined as EDV(2). This method is based on subtraction of the calculated brain concentrations of the FDOPA metabolite O-methyl-FDOPA, rather than the subtraction of the entire radioactivity in a reference region. We now extend this method for the parametric mapping of these parameters in the brain of healthy aged volunteers and patients with Parkinson's disease (PD), with asymmetry of motor symptoms. For parametric mapping, we use a novel application of a multilinear solution for the two-tissue compartment FDOPA model. We also test a new application of the Logan graphical analysis for mapping of the FDOPA distribution volume at equilibrium. The estimates of k(loss) and EDV(2) were more sensitive for the discrimination of biochemical abnormality in the putamen of patients with early PD relative to healthy aged subjects, than was the conventional net influx estimate. Of the several methods, multilinear estimates of EDV(2) were most sensitive for discrimination of PD and normal putamen. However, k(loss) was most sensitive for detecting biochemical asymmetry in the putamen of PD patients, and only k(loss) also detected in the caudate of PD patients a decline in the retention of [(18)F]fluorodopamine relative to healthy aged control subjects.

Vesicular monoamine transporter-2 and aromatic l-amino acid decarboxylase gene therapy prevents development of motor complications in parkinsonian rats after chronic intermittent l-3,4-dihydroxyphenylalanine administration

Motor complications after chronic l-3,4-dihydroxyphenylalanine ( l-DOPA) therapy occur partly because of the sensitization to dopaminergic agents resulting from pulsatile dopaminergic stimulation. The loss of presynaptic storage contributes to short duration of action by dopamine. Vesicular monoamine transporter-2 (VMAT-2) controls intraneuronal dopamine storage by packaging dopamine into synaptic vesicles, thereby allowing exocytotic release of dopamine. Using primary fibroblast doubly transduced with VMAT-2 and aromatic l-amino acid decarboxylase (AADC) genes, we previously demonstrated the beneficial effects of such double gene transduction in the production, storage, and gradual release of dopamine in vitro and in vivo. In this study, we further evaluate the effect of achieving sustained level of dopamine within the striata by VMAT-2 gene on behavioral response of parkinsonian rats after chronic intermittent l-DOPA administration. Primary fibroblast (PF) cells were genetically modified with AADC and VMAT-2 genes. We grafted primary fibroblast cells, PF with AADC (PFAADC), or doubly transduced PF with AADC and VMAT-2 (PFVMAA) ( n = 6 for each group) into parkinsonian rat striata and administered l-DOPA (25 mg/kg/day) intermittently for 4 weeks. For behavioral study, we employed a model of akinesia using forepaw adjusting steps (FAS) that have been well characterized to reflect the effect of the lesion and the antiparkinsonian effect of dopaminergic drugs and transplants. The duration of FAS response to l-DOPA was sustained for a longer duration in rats grafted with PFVMAA cells than in those grafted with either control cells or cells with AADC alone. In PFVMAA-grafted animals, prolonged duration of FAS responses to l-DOPA was sustained even 6 weeks after discontinuation of 4-week intermittent l-DOPA treatment. These findings suggest that the restoration of dopamine storage capacity could enhance the efficacy of l-DOPA therapy and attenuate the motor fluctuations that result from chronic intermittent l-DOPA administration. The gene therapy expressing AADC and VMAT-2 along with systemic l-DOPA therapy could provide a novel treatment strategy to prevent motor fluctuations.