Subrata K. Bose

Inflammation after trauma: Microglial activation and traumatic brain injury

Patient outcome after traumatic brain injury (TBI) is highly variable. The underlying pathophysiology of this is poorly understood, but inflammation is potentially an important factor. Microglia orchestrate many aspects of this response. Their activation can be studied in vivo using the positron emission tomography (PET) ligand [11C](R)PK11195 (PK). In this study, we investigate whether an inflammatory response to TBI persists, and whether this response relates to structural brain abnormalities and cognitive function.

Dopamine Synthesis Capacity Before Onset of Psychosis: A Prospective [18F]-DOPA PET Imaging Study

OBJECTIVE While there is robust evidence of elevated dopamine synthesis capacity once a psychotic disorder has developed, little is known about whether it is altered prior to the first episode of frank illness. The authors addressed this issue by measuring dopamine synthesis capacity in individuals at ultra-high risk of psychosis and then following them to determine their clinical outcome. METHOD This prospective study included 30 patients who met standard criteria for being at ultra-high risk of psychosis and 29 healthy volunteers. Participants were scanned using [(18)F]6-fluoro-L-dopa positron emission tomography. The ultra-high-risk patients were scanned at presentation and followed up for at least 3 years to determine their clinical outcome. Six patients had comorbid schizotypal personality disorder and were excluded from the analysis (data are provided for comparison). Of the remaining patients, nine developed a psychotic disorder (psychotic transition group) and 15 did not (nontransition group). RESULTS There was a significant effect of group on striatal dopamine synthesis capacity. The psychotic transition group had greater dopamine synthesis capacity in the striatum (effect size=1.18) and its associative subdivision (effect size=1.24) than did the healthy comparison subjects and showed a positive correlation between dopamine synthesis capacity and symptom severity. Dopamine synthesis capacity was also significantly greater in the psychotic transition group than in the nontransition group. CONCLUSIONS These findings provide evidence that the onset of frank psychosis is preceded by presynaptic dopaminergic dysfunction. Further research is needed to determine the specificity of elevated dopamine synthesis capacity to particular psychotic disorders.

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 Parkinsons 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 Parkinsons disease is associated with dopaminergic and serotonergic dysfunction in basal ganglia and limbic circuits. Ten patients with Parkinsons 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 Parkinsons 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 Parkinsons disease and may also be relevant to alleviating fatigue in other clinical conditions.

Cue-induced striatal dopamine release in Parkinson's disease-associated impulsive-compulsive behaviours

Impulsive-compulsive behaviours are a significant source of morbidity for patients with Parkinsons disease receiving dopaminergic therapy. The development of these behaviours may reflect sensitization of the neural response to non-drug rewards, similar to that proposed for sensitization to drug rewards in addiction. Here, by using (11)C-raclopride positron emission tomography imaging, we investigated the effects of reward-related cues and L-dopa challenge in patients with Parkinsons disease with and without impulsive-compulsive behaviours on striatal levels of synaptic dopamine. Eighteen patients (11 with and seven without impulsive-compulsive behaviours) underwent three (11)C-raclopride positron emission tomography scans. The impulsive-compulsive behaviours included hypersexuality, binge eating, punding, compulsive use of dopamine replacement therapy, compulsive buying and pathological gambling, with eight patients exhibiting more than one impulsive-compulsive behaviour. There were no significant differences in baseline dopamine D2 receptor availability between the Parkinsons disease groups. No differences were found when comparing the percentage change of raclopride binding potential between the two Parkinsons disease groups following L-dopa challenge with neutral cues. The group with Parkinsons disease with impulsive-compulsive behaviours had a greater reduction of ventral striatum (11)C-raclopride binding potential following reward-related cue exposure, relative to neutral cue exposure, following L-dopa challenge (16.3% compared with 5.8% in Parkinsons disease controls, P = 0.016). The heightened response of striatal reward circuitry to heterogeneous reward-related visual cues among a group of patients with different impulsive-compulsive behaviours is consistent with a global sensitization to appetitive behaviours with dopaminergic therapy in vulnerable individuals. Our findings are relevant for the broader debate on the relation between impulsive-compulsive behaviours and addictions and may have important implications with regards to advertisement legislation in an effort to prevent the onset of behavioural addictions.

Progressive increase in striatal dopamine synthesis capacity as patients develop psychosis: a PET study

Progressive increase in striatal dopamine synthesis capacity as patients develop psychosis: a PET study

Adenosine 2A receptor availability in dyskinetic and nondyskinetic patients with Parkinson disease

Objective: To investigate striatal adenosine A2A receptor availability in patients with Parkinson disease (PD) with and without levodopa-induced dyskinesias (LIDs). While providing effective relief from the motor symptoms of PD, chronic levodopa use is associated with development of LIDs. A2A receptors are expressed on the bodies of indirect pathway medium spiny striatal neurons and on dopamine terminals and play a role in modulating dopamine transmission. A2A antagonists have antiparkinsonian activity by boosting levodopa efficacy. We aimed to study A2A receptor availability in patients with PD with and without LIDs using PET and [11C]SCH442416, an A2A antagonist. Methods: Six patients with PD with and 6 without LIDs were studied withdrawn 12 hours from medication. Their PET findings were compared with 6 age-matched healthy controls. Using spectral analysis, [11C]SCH442416 regional volumes of distribution (VT) were computed for the caudate, putamen, and thalamus and binding potentials (BPND) reflecting the ratio of specific:nonspecific uptake were compared between groups. Results: A2A binding in the caudate and putamen of subjects with PD with LIDs was far higher (p = 0.026 and p = 0.036, respectively) than that of subjects with PD without LIDs, which lay within the control range. Thalamic A2A availability was similar for all 3 groups. Conclusion: Patients with PD with LIDs show increased A2A receptor availability in the striatum. This finding is compatible with altered adenosine transmission playing a role in LIDs and provides a rationale for a trial of A2A receptor agents in the treatment of these motor complications.

Classification of schizophrenic patients and healthy controls using [18F] fluorodopa PET imaging

Striatal dopaminergic overactivity has been implicated in the pathophysiology of schizophrenia on the basis of in vivo neuroimaging studies. In particular, elevated striatal dopamine synthesis and storage has been repeatedly demonstrated in schizophrenia using the radiotracer 6-[18F] fluoro-l-DOPA ([18F] DOPA) and positron emission tomography (PET). Conventionally analysed [18F] DOPA PET imaging lacks the sensitivity or specificity to be used diagnostically. The aim of this study was to determine if the application of an Artificial Neural Network (ANN) would improve classification of images, and increase the sensitivity and specificity of [18F] DOPA as a potential diagnostic test for schizophrenia. We tested an ANN model in the discrimination of schizophrenic patients from normal controls using [18F] DOPA rate constants within the anterior-posterior subdivisions of the striatum, and compared the model with a general linear analysis of the same data. Participating in the study were 19 patients diagnosed with paranoid schizophrenia and 31 healthy subjects. Maximum classification was achieved using laterality quotients, - the ANN model correctly identified 94% of the controls and 89% of the patients, equivalent to 89% sensitivity and 94% specificity. Using all bilateral striatal regions correctly categorised 74% of the controls and 84% of the patients, equivalent to 84% sensitivity and 74% specificity. In comparison, the general linear analysis performed poorly, correctly classifying only 58% of the controls and 63% of the patients. Overall, these analyses have shown the potential utility of pattern recognition tools in the classification of psychiatric patients based upon molecular imaging of a single target.

The catechol-O-methyltransferase Val158Met polymorphism modulates fronto-cortical dopamine turnover in early Parkinson’s disease: a PET study

Cognitive deficits occur in up to 30% of patients with early Parkinsons disease, some of which are thought to result from dysfunction within the fronto-striatal dopaminergic network. Recently, it has been shown that a common functional polymorphism (Val(158)Met) in the catechol-O-methyltransferase (COMT) gene is associated with changes in executive performance in tasks that have a fronto-striatal basis. This is thought to relate to changes in cortical dopamine levels as catechol-O-methyltransferase is the main mode of inactivation for dopamine in frontal areas. However to date, no study has investigated dopamine turnover as a function of this genetic polymorphism in Parkinsons disease. We, therefore, set out to investigate in vivo changes in presynaptic dopamine storage in patients with idiopathic Parkinsons disease as a function of the catechol-O-methyltransferase Val(158)Met polymorphism using (18)F-DOPA positron emission tomography. Twenty patients with Parkinsons disease (10 homozygous for Val/Val and 10 for Met/Met catechol-O-methyltransferase polymorphisms) underwent (18)F-DOPA positron emission tomography using a prolonged imaging protocol. The first dynamic scan was acquired from 0 to 90 min (early), and the second scan (late) from 150 to 210 min post-intravenous radioligand administration. Patients were matched for age, sex, verbal IQ, disease duration and severity of motor features. (18)F-DOPA influx constants (Ki) were calculated and compared for frontal and striatal regions. Late scan mean frontal and striatal Ki values were significantly reduced in both Parkinsons disease groups relative to early scan Ki values. Met/Met patients had significantly higher late scan Ki values compared with their Val/Val counterparts in anterior cingulate, superior frontal and mid-frontal regions but early frontal Ki values were not different between the two groups. As late Ki values reflect rates of dopamine metabolism to 3,4-dihydroxyphenylacetic acid and homovanillic acid, our results indicate that Met homozygotes have higher presynaptic dopamine levels in frontal regions than Val homozygotes, which may help to explain how this genotypic variation may influence the fronto-striatal cognitive deficits of Parkinsons disease.

Striatal dopamine synthesis capacity in twins discordant for schizophrenia

BACKGROUND Elevated striatal dopamine synthesis capacity is thought to be fundamental to the pathophysiology of schizophrenia and has also been reported in people at risk of psychosis. It is therefore unclear if striatal hyperdopaminergia is a vulnerability marker for schizophrenia, or a state feature related to the psychosis itself. Relatives of patients with schizophrenia are themselves at increased risk of developing the condition. In this study we examined striatal dopamine synthesis capacity in both members of twin pairs discordant for schizophrenia. METHOD In vivo striatal dopamine synthesis capacity was examined using fluorine-18-l-dihydroxyphenylalanine (18F-DOPA) positron emission tomography (PET) scans in seven twin pairs discordant for schizophrenia and in a control sample of 10 healthy control twin pairs. RESULTS Striatal 18F-DOPA uptake was not elevated in the unaffected co-twins of patients with schizophrenia (p=0.65) or indeed in the twins with schizophrenia (p=0.89) compared to the control group. Levels of psychotic symptoms were low in the patients with schizophrenia who were in general stable [mean (s.d.) Positive and Negative Syndrome Scale (PANSS) total=56.8 (25.5)] whereas the unaffected co-twins were largely asymptomatic. CONCLUSIONS Striatal dopamine synthesis capacity is not elevated in symptom-free individuals at genetic risk of schizophrenia, or in well-treated stable patients with chronic schizophrenia. These findings suggest that striatal hyperdopaminergia is not a vulnerability marker for schizophrenia.

Increased frontoparietal integration after stroke and cognitive recovery.

The neural mechanism by which patients spontaneously recover cognitive function after brain injury is not understood. Here we demonstrate for the first time that aphasic patients, who have largely recovered language function, show increased frontoparietal integration. A similar change in functional connectivity is also observed when normal subjects are exposed to adverse listening conditions. Thus, compensation for inefficient language processing is associated with increased integration between parts of the language network critical to language control. This change reflects greater top‐down control of speech comprehension and provides a mechanism by which language impairments after stroke may be compensated for. ANN NEUROL 2010