In vivo imaging of synaptic SV2A protein density in healthy and striatal-lesioned rats with [11C]UCB-J PET.

The number of functionally active synapses provides a measure of neural integrity, with reductions observed in neurodegenerative disorders. [11C]UCB-J binds to synaptic vesicle 2A (SV2A) transmembrane protein located in secretory vesicles. We aimed to assess [11C]UCB-J PET as an in vivo biomarker of regional cerebral synaptic SV2A density in rat lesion models of neurodegeneration. Healthy anesthetized rats had [11C]UCB-J PET and arterial blood sampling. We compared different models describing [11C]UCB-J brain uptake kinetics to determine its regional distribution. Blocking studies were performed with levetiracetam (LEV), an antiepileptic SV2A antagonist. Tracer binding was measured in rodent unilateral acute lesion models of Parkinsonism and Huntington's disease, induced with 6-hydroxydopamine (6-OHDA) and quinolinic acid (QA), respectively. [3H]UCB-J autoradiography was performed in postmortem tissue. Rat brain showed high and fast [11C]UCB-J uptake and washout with up to 80% blockade by LEV. [11C]UCB-J PET showed a 6.2% decrease in ipsilateral striatal SV2A binding after 6-OHDA and 39.3% and 55.1% decreases after moderate and high dose QA confirmed by autoradiography. In conclusion, [11C]UCB-J PET provides a good in vivo marker of synaptic SV2A density which can potentially be followed longitudinally along with synaptic responses to putative neuroprotective agents in models of neurodegeneration.

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

INTRODUCTION: Noradrenergic 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. METHODS: 17 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. RESULTS: Partial-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). CONCLUSIONS: This 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.

Attenuation of dopamine-induced GABA release in problem gamblers.

INTRODUCTION: We have previously shown that an interaction between medial prefrontal and parietal cortices is instrumental in promoting self-awareness via synchronizing oscillations in the gamma range. The synchronization of these oscillations is modulated by dopamine release. Given that such oscillations result from intermittent GABA stimulation of pyramidal cells, it is of interest to determine whether the dopaminergic system regulates GABA release directly in cortical paralimbic regions. Here, we test the hypothesis that the regulation of the GABA-ergic system by the dopaminergic system becomes attenuated in problem gamblers resulting in addictive behaviors and impaired self-awareness. METHODS: [11 C]Ro15-4513 PET, a marker of benzodiazepine α1/α5 receptor availability in the GABA receptor complex, was used to detect changes in synaptic GABA levels after oral doses of 100mg L-dopa in a double-blind controlled study of male problem gamblers (N = 10) and age-matched healthy male controls (N = 10). RESULTS: The mean reduction of cortical gray matter GABA/BDZ receptor availability induced by L-dopa was significantly attenuated in the problem gambling group compared to the healthy control group (p = 0.0377). CONCLUSIONS: Our findings demonstrate that: (a) Exogenous dopamine can induce synaptic GABA release in healthy controls. (b) This release is attenuated in frontal cortical areas of males suffering from problem gambling, possibly contributing to their loss of inhibitory control. This suggests that dysfunctional dopamine regulation of GABA release may contribute to problem gambling and gambling disorder.

The Effect of 40-Hz Light Therapy on Amyloid Load in Patients with Prodromal and Clinical Alzheimer's Disease.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder. AD pathology is characterized by abnormal aggregation of the proteins amyloid-ß (Aß) and hyperphosphorylated tau. No effective disease modifying therapies are currently available. A short-duration intervention with 40 Hz light flicker has been shown to reduce brain Aß load in transgenic mice. We aimed to test the effect of a similar short-duration 40 Hz light flicker regime in human AD patients. We utilized a Light Emitting Diode (LED) light bulb with a 40 Hz flicker. Six Aß positive patients received 10 days of light therapy, had 2 hours of daily exposure, and underwent a postintervention PiB PET on day 11. After 10 days of light therapy, no significant decrease of PiB SUVR values was detected in any volumes of interest tested (primary visual cortex, visual association cortex, lateral parietal cortex, precuneus, and posterior cingulate) or in the total motor cortex, and longer treatments may be necessary to induce amyloid removal in humans.

Extrastriatal monoaminergic dysfunction and enhanced microglial activation in idiopathic rapid eye movement sleep behaviour disorder.

BACKGROUND: The majority of patients diagnosed with idiopathic rapid eye movement sleep behaviour disorder (iRBD) progress over time to a Lewy-type α-synucleinopathy such as Parkinson's disease or dementia with Lewy bodies. This in vivo molecular imaging study aimed to investigate if extrastriatal monoaminergic systems are affected in iRBD patients and if this coincides with neuroinflammation. METHODS: We studied twenty-one polysomnography-confirmed iRBD patients with 18F-DOPA and 11C-PK11195 positron emission tomography (PET) to investigate extrastriatal monoaminergic function and microglial activation. Twenty-nine healthy controls (n = 9 18F-DOPA and n = 20 11C-PK11195) were also investigated. Analyses were performed within predefined regions of interest and at voxel-level with Statistical Parametric Mapping. RESULTS: Regions of interest analysis detected monoaminergic dysfunction in iRBD thalamus with a 15% mean reduction of 18F-DOPA Ki values compared to controls (mean difference = -0.00026, 95% confidence interval [-0.00050 to -0.00002], p-value = 0.03). No associated thalamic changes in 11C-PK11195 binding were observed. Other regions sampled showed no 18F-DOPA or 11C-PK11195 PET differences between groups. Voxel-level interrogation of 11C-PK11195 binding identified areas with significantly increased binding within the occipital lobe of iRBD patients. CONCLUSION: Thalamic monoaminergic dysfunction in iRBD patients may reflect terminal dysfunction of projecting neurons from the locus coeruleus and dorsal raphe nucleus, two structures that regulate REM sleep and are known to be involved in the early phase of PD. The observation of significantly raised microglial activation in the occipital lobe of these patients might suggest early local Lewy-type α-synuclein pathology and possibly an increased risk for later cognitive dysfunction.

Hypothalamic volume loss is associated with reduced melatonin output in Parkinson's disease.

BACKGROUND: Recent studies have suggested that melatonin-a hormone produced by the pineal gland under circadian control-contributes to PD-related sleep dysfunction. We hypothesized that degenerative changes to the neural structures controlling pineal function (especially the suprachiasmatic nuclei of the anterior hypothalamus) may be responsible for reduced melatonin output in these patients. We compared hypothalamic volumes in PD patients with matched controls and determined whether volume loss correlated with reduced melatonin output in the PD group. METHODS: A total of 12 PD patients and 12 matched controls underwent magnetic resonance imaging to determine hypothalamic volume. In addition, PD patients underwent 24-hour blood sampling in a controlled environment to determine serum melatonin concentrations using enzyme-linked immunosorbent assays. RESULTS: PD patients had significantly reduced hypothalamic gray matter volume when compared with matched controls. Melatonin levels were significantly associated with hypothalamic gray matter volume and disease severity in PD patients. CONCLUSION: Melatonin levels are associated with hypothalamic gray matter volume loss and disease severity in PD patients. This provides anatomical and physiological support for an intrinsic sleep and circadian phenotype in PD. © 2016 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.

Thalamic inflammation after brain trauma is associated with thalamo-cortical white matter damage.

BACKGROUND: Traumatic brain injury can trigger chronic neuroinflammation, which may predispose to neurodegeneration. Animal models and human pathological studies demonstrate persistent inflammation in the thalamus associated with axonal injury, but this relationship has never been shown in vivo. FINDINGS: Using [(11)C]-PK11195 positron emission tomography, a marker of microglial activation, we previously demonstrated thalamic inflammation up to 17 years after traumatic brain injury. Here, we use diffusion MRI to estimate axonal injury and show that thalamic inflammation is correlated with thalamo-cortical tract damage. CONCLUSIONS: These findings support a link between axonal damage and persistent inflammation after brain injury.

Inflammation after trauma: microglial activation and traumatic brain injury.

OBJECTIVE: 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. METHODS: Ten patients, studied at least 11 months after moderate to severe TBI, underwent PK PET and structural magnetic resonance imaging (including diffusion tensor imaging). PK binding potentials were calculated in and around the site of focal brain damage, and in selected distant and subcortical brain regions. Standardized neuropsychological tests were administered. RESULTS: PK binding was significantly raised in the thalami, putamen, occipital cortices, and posterior limb of the internal capsules after TBI. There was no increase in PK binding at the original site of focal brain injury. High PK binding in the thalamus was associated with more severe cognitive impairment, although binding was not correlated with either the time since the injury or the extent of structural brain damage. INTERPRETATION: We demonstrate that increased microglial activation can be present up to 17 years after TBI. This suggests that TBI triggers a chronic inflammatory response particularly in subcortical regions. This highlights the importance of considering the response to TBI as evolving over time and suggests interventions may be beneficial for longer intervals after trauma than previously assumed.

GABAergic dysfunction in essential tremor: an 11C-flumazenil PET study.

UNLABELLED: Essential tremor is the most common movement disorder, but the underlying pathophysiology is not well understood. A primary overactivity of cerebellothalamic output pathways is the most conspicuous finding, as indicated by animal and human studies. It has been argued that this overactivity may be due to impaired central inhibition, and converging evidence points toward a potential role of gamma-aminobutyric acid (GABA) dysfunction in tremor generation. METHODS: Using (11)C-flumazenil and PET, we calculated the distribution volume, an index of availability of benzodiazepine receptor sites of the GABA(A) complex, in a group of 8 patients with bilateral essential tremor, as compared with 11 healthy controls. RESULTS: Significant increases in binding of (11)C-flumazenil at the benzodiazepine receptor site of the GABA(A) receptor in the cerebellum, the ventrolateral thalamus, and the lateral premotor cortex were identified in the essential tremor group. CONCLUSION: Essential tremor is associated with reduced GABAergic function and increased availability of benzodiazepine receptor sites in brain regions implicated specifically in tremor genesis. This finding is thought to reflect overactivity of cerebellothalamic circuits and, hence, lends support to the "GABA hypothesis" of essential tremor.

Evidence of dopamine dysfunction in the hypothalamus of patients with Parkinson's disease: an in vivo 11C-raclopride PET study.

A mild to moderate reduction in dopamine, noradrenaline and serotonin levels alongside a progressive loss of hypocretin cells and melanin hormone concentrating cells has been reported in the hypothalamus of PD at postmortem. Hypothalamic uptake of (18)F-dopa PET, an in vivo marker of dysfunction of monoaminergic neurons, is also significantly reduced in these patients. These data indicate a general impairment of hypothalamic function in PD. Dopamine receptors play an important role in the regulation of hypothalamic pathways. To date, possible changes in hypothalamic D(2) receptor availability have not been investigated in PD. The objective in this study was to assess dopamine D(2) receptor availability in hypothalamus of patients with idiopathic Parkinson's disease (PD) using positron emission tomography (PET) with (11)C-raclopride (RAC). We evaluated D(2) binding in RAC PET images of 14 PD patients using both region of interest (ROI) analysis and a voxel based approach. ROIs for the hypothalamus were traced on the subject's MRI co-registered to the PET image. (11)C-raclopride binding potentials (BP) for hypothalamus were obtained by applying ROIs onto parametric images. Findings were compared with those of 9 normal controls. We found a significant reduction in the mean hypothalamic RAC BP of the PD patients compared with the normal controls (0.2714+/-0.06 vs. 0.3861+/-0.04; mean+/-SD; p=0.0005). ROI results were confirmed with statistical parametric mapping (SPM). Individual hypothalamic BP values of PD patients did not correlate with age, disease duration, disease severity and levodopa equivalent dose. It remains to be ascertained whether the reductions in hypothalamic D(2) receptor availability seen in PD are disease related, the results of chronic exposure to levodopa or both. Our results provide further evidence of dopaminergic dysfunction in the hypothalamus in PD, and this may contribute to the development of sleep, endocrine and autonomic disorders.

Volumetric cortical loss in sporadic and familial amyotrophic lateral sclerosis.

Patients homozygous for the D90A mutation of the SOD1 gene (homD90A) demonstrate markedly slower progression of disease than those patients with sporadic ALS (SALS). PET studies have demonstrated a different cortical vulnerability in the two groups, reflected also in neurophysiological studies showing reduced cortical excitability in homD90A. Voxel-based morphometric analysis of magnetic resonance images (MRIs) enables the detection of regional differences in grey matter volume, and can be used to localize cortical atrophy in vivo. In this study, segmented, spatially normalized, modulated and smoothed grey matter portions of the MRIs from 23 SALS and seven homD90A patients with similar disability, were compared with those from 28 healthy control subjects. The SALS group showed bilateral areas of atrophy mainly confined to motor and pre-motor cortices. Cortical changes in the homD90A group were more pronounced within the frontal lobes when both were compared with healthy controls. This study provides further evidence for a different pattern of cortical neuronal vulnerability in homD90A versus SALS patients that may provide insight as to their slower rate of disease progression.

Volumes, spatial extents and a probabilistic atlas of the human basal ganglia and thalamus.

The basal ganglia and thalamus are involved in processing all physiological behaviors and affected by many diseases. Accurate localization is a crucial issue in neuroimaging, particularly when working with groups of normalized images in a standard stereotaxic space. Here, manual delineation of the central structures (thalamus; nucleus caudatus and accumbens; putamen, pallidum, substantia nigra) was performed on 30 high resolution MRIs of healthy young adults (15 female, median age 31 years) in native space. Protocol inter-rater reliabilities were quantified as structure overlap (similarity indices, SIs). Structural volumes were calculated in native space, and after spatial normalization to stereotaxic space (MNI/ICBM152) and in relation to hemispheric volumes. Spatial extents relative to the anterior commissure (AC) were extracted. The 30 resulting atlases were then used to create probabilistic maps in stereotaxic space. Inter-rater SIs were high at 0.85-0.92 except for the nucleus accumbens. In native space, caudate, nucleus accumbens and putamen were significantly larger on the left, and the globus pallidus larger in males. After normalizing for brain volume, the nucleus accumbens, putamen and thalamus were larger on the left, with the gender difference in the globus pallidus still detectable. Some of these volume differences translated into significantly different distances from the AC. The probabilistic maps showed that overall the central structures' boundaries are relatively unchanged after spatial normalization. We present a comprehensive assessment of thalamic and basal ganglia volumetric and geometric data in both native and stereotaxic spaces. Probabilistic maps in MNI/ICBM152 space will allow accurate localization in group analyses.

Dopaminergic action beyond its effects on motor function: imaging studies.

Along with motor programming, it is now thought that tonic release of dopamine in the striatum acts to focus and filter non-motor activities such as working memory, implicit learning, decision making, and planning. Additionally, thresholds to painful stimuli may well be dopamine dependant. Phasic (burst) release of dopamine in the basal ganglia and frontal areas is thought to play a role in alerting organisms to novel and potentially rewarding stimuli and in mediating contextual learning. Dopamine release also drives a craving for stimuli and facilitates their enjoyment. Functional imaging can help elucidate the role of dopamine in mediating non-motor activities. The integrity of dopamine terminal function can be measured with PET and SPECT in vivo in health and Parkinson's disease (PD) and this can be correlated with performance of executive tasks. In addition, these imaging modalities allow dopamine release in response to stimuli (both rewarding and unrewarding) to be detected, as reflected by changes in D2 receptor availability to radioligands. Finally, the functional effects of dopamine deficiency and its replacement can be monitored by studying patterns of brain activation, as evidenced by regional blood flow changes. In this review, some of the insights that imaging has given us concerning the role of dopamine in non-motor functions is presented.