A spatial covariance 123I-5IA-85380 SPECT study of α4ß2 nicotinic receptors in Alzheimer's disease.

Alzheimer's disease (AD) is characterized by widespread degeneration of cholinergic neurons, particularly in the basal forebrain. However, the pattern of these deficits and relationship with known brain networks is unknown. In this study, we sought to clarify this and used 123I-5-iodo-3-[2(S)-2-azetidinylmethoxy] pyridine (1235IA-85380) single photon emission computed tomography to investigate spatial covariance of α4ß2 nicotinic acetylcholine receptors in AD and healthy controls. Thirteen AD and 16 controls underwent 1235IA-85380 and regional cerebral blood flow (99mTc-exametazime) single photon emission computed tomography scanning. We applied voxel principal component (PC) analysis, generating series of principal component images representing common intercorrelated voxels across subjects. Linear regression generated specific α4ß2 and regional cerebral blood flow covariance patterns that differentiated AD from controls. The α4ß2 pattern showed relative decreased uptake in numerous brain regions implicating several networks including default mode, salience, and Papez hubs. Thus, as well as basal forebrain and brainstem cholinergic system dysfunction, cholinergic deficits mediated through nicotinic acetylcholine receptors could be evident within key networks in AD. These findings may be important for the pathophysiology of AD and its associated cognitive and behavioral phenotypes.

Cholinergic and perfusion brain networks in Parkinson disease dementia.

OBJECTIVE: To investigate muscarinic M1/M4 cholinergic networks in Parkinson disease dementia (PDD) and their association with changes in Mini-Mental State Examination (MMSE) after 12 weeks of treatment with donepezil. METHODS: Forty-nine participants (25 PDD and 24 elderly controls) underwent (123)I-QNB and (99m)Tc-exametazime SPECT scanning. We implemented voxel principal components (PC) analysis, producing a series of PC images of patterns of interrelated voxels across individuals. Linear regression analyses derived specific M1/M4 and perfusion spatial covariance patterns (SCPs). RESULTS: We found an M1/M4 SCP of relative decreased binding in basal forebrain, temporal, striatum, insula, and anterior cingulate (F1,47 = 31.9, p < 0.001) in cholinesterase inhibitor-naive patients with PDD, implicating limbic-paralimbic and salience cholinergic networks. The corresponding regional cerebral blood flow SCP showed relative decreased uptake in temporoparietal and prefrontal areas (F1,47 = 177.5, p < 0.001) and nodes of the frontoparietal and default mode networks (DMN). The M1/M4 pattern that correlated with an improvement in MMSE (r = 0.58, p = 0.005) revealed relatively preserved/increased pre/medial/orbitofrontal, parietal, and posterior cingulate areas coinciding with the DMN and frontoparietal networks. CONCLUSION: Dysfunctional limbic-paralimbic and salience cholinergic networks were associated with PDD. Established cholinergic maintenance of the DMN and frontoparietal networks may be prerequisite for cognitive remediation following cholinergic treatment in this condition.

Regional covariance of muscarinic acetylcholine receptors in Alzheimer's disease using (R, R) [(123)I]-QNB SPECT.

Alzheimer's disease (AD) is characterised by deficits in cholinergic neurotransmission and subsequent receptor changes. We investigated (123)I-iodo-quinuclidinyl-benzilate (QNB) SPECT images using spatial covariance analysis (SCA), to detect an M1/M4 receptor spatial covariance pattern (SCP) that distinguished AD from controls. Furthermore, a corresponding regional cerebral blood flow (rCBF) SCP was also derived. Thirty-nine subjects (15 AD and 24 healthy elderly controls) underwent (123)I-QNB and (99m)Tc-exametazime SPECT. Voxel SCA was simultaneously applied to the set of smoothed/registered scans, generating a series of eigenimages representing common intercorrelated voxels across subjects. Linear regression identified individual M1/M4 and rCBF SCPs that discriminated AD from controls. The M1/M4 SCP showed concomitant decreased uptake in medial temporal, inferior frontal, basal forebrain and cingulate relative to concomitant increased uptake in frontal poles, occipital, pre-post central and precuneus/superior parietal regions (F1,37 = 85.7, p < 0.001). A largely different perfusion SCP was obtained showing concomitant decreased rCBF in medial and superior temporal, precuneus, inferior parietal and cingulate relative to concomitant increased rCBF in cerebellum, pre-post central, putamen, fusiform and brain stem/midbrain regions (F1,37 = 77.5, p < 0.001). The M1/M4 SCP expression correlated with the duration of cognitive symptoms (r = 0.90, p < 0.001), whereas the rCBF SCP expression negatively correlated with MMSE, CAMCOG and CAMCOGmemory (r ≥ |0.63|, p ≤ 0.006). (123)I-QNB SPECT revealed an M1/M4 basocortical covariance pattern, distinct from rCBF, reflecting the duration of disease rather than current clinical symptoms. This approach could be more sensitive than univariate methods in characterising the cholinergic/rCBF changes that underpin the clinical phenotype of AD.

Assessment of [125I]WYE-230949 as a novel histamine H3 receptor radiopharmaceutical.

Histamine H3 receptor therapeutics have been proposed for several diseases such as schizophrenia, attention deficit hyperactivity disorder, Alzheimer's disease and obesity. We set out to evaluate the novel compound, [125I]WYE-230949, as a potential radionuclide imaging agent for the histamine H3 receptor in brain. [125I]WYE-230949 had a high in vitro affinity for the rat histamine H3 receptor (Kd of 6.9 nM). The regional distribution of [125I]WYE-230949 binding sites in rat brain, demonstrated by in vitro autoradiography, was consistent with the known distribution of the histamine H3 receptor. Rat brain uptake of intravenously injected [125I]WYE-230949 was low (0.11 %ID/g) and the ratio of specific: non-specific binding was less than 1.4, as determined by ex vivo autoradiography. In plasma, metabolism of [125I]WYE-230949 into a less lipophilic species occurred, such that less than 38% of the parent compound remained 30 minutes after injection. Brain uptake and metabolism of [125I]WYE-230949 were increased and specific binding was reduced in anaesthetised compared to conscious rats. [125I]WYE230949 is not a potential radiotracer for imaging rat histamine H3 receptors in vivo due to low brain uptake, in vivo metabolism of the parent compound and low specific binding.

Nicotinic 123I-5IA-85380 single photon emission computed tomography as a predictor of cognitive progression in Alzheimer's disease and dementia with Lewy bodies.

OBJECTIVE: To investigate normalized I-5-Iodo-3-[2(S)-2-azetidinylmethoxy] pyridine (5IA-85380) single photon emission computed tomography (SPECT) imaging, a marker for the alpha4beta2 nicotinic receptor, as a predictor of cognitive progression in Alzheimer's disease (AD) and dementia with Lewy bodies (DLB). METHODS: Thirty-one patients with dementia (16 patients with AD and 15 patients with DLB) underwent I-5IA-85380 SPECT scanning. Image analysis was performed using statistical parametric mapping (SPM2), which involved spatial preprocessing of scans to standard Montreal Neurological Institute space and intensity normalization of each image to its mean global brain activity. RESULTS: Regression analysis revealed that reduced normalized I-5IA-85380 uptake in left superior, middle, and inferior frontal gyri and prepost central and anterior cingulate regions significantly correlated with decline in executive function in a pooled group comprising AD and DLB. CONCLUSION: The findings, although preliminary, suggest that the cholinergic system may be more involved in neurodegenerative processes affecting some cognitive processes more than others, as such, this procedure may be useful for increased understanding of the pathophysiological mechanisms responsible for neurodegeneration.

SSRI antidepressants do not confound single photon emission computed tomography (SPECT) imaging studies using the alpha4beta2 nicotinic acetylcholine receptor [123I]5-I-A85380 ligand: in vivo and in vitro evidence.

PURPOSE: In clinical molecular imaging the interaction between antidepressant medication and SPECT ligands is a significant potential confound. This study measured nAChR availability, as determined by SPECT imaging, on and off selective serotonin reuptake inhibitors in first episode depressed patients. METHODS: Five patients in their first episode of major depressive disorder (MDD) on a single SSRI underwent [(123)I]5-I-A85380- SPECT neuroimaging prior to stopping their medication and again 6 weeks following medication cessation. Autoradiography of post mortem brain tissue with [(125)I]5-I-A85380 in the presence or absence of four commonly prescribed antidepressants was also assessed. RESULTS: SSRI antidepressants did not affect the relative binding availability of alpha4beta2 nicotinic acetylcholine receptors for the [(123)I]5-I-A85380 ligand in vivo. Radioligand binding in vitro was unaffected by a single, high pharmacological concentration of antidepressants. CONCLUSION: SPECT imaging studies using [(123)I]5-I-A85380 to measure alpha4beta2 nAChR availability in depressed patients are unlikely to be confounded to a major degree by concurrent antidepressant medication.

5-(123)I-A-85380 binding to the α4ß2-nicotinic receptor in mild cognitive impairment.

Treatments currently licensed for Alzheimer's dementia target cholinergic brain systems. In vivo nicotinic receptor binding may provide an early marker of illness and treatment suitability. In this pilot, we examined nine patients with amnestic mild cognitive impairment (MCI) and 10 age and education matched healthy volunteers with high resolution SPECT and the nicotinic receptor ligand 5-(123)I-A-85380. Uptake data were analysed using voxel-based techniques for group comparisons and regression analyses with cognitive impairment as covariates. MCI patients had discrete reductions in uptake in medial temporal cortex. Correlations with cognitive impairment were found in left temporo-parietal areas (Addenbrooke's Cognitive Examination) and bilateral temporo-limbic areas (Rey Auditory Verbal Learning Test), and right parahippocampal gyrus (Rey Complex Figure Test) within the patient group. In vivo nicotinic receptor binding appears to be sensitive to brain changes in MCI. Larger scale explorations of patients undergoing treatment will be necessary to evaluate its use in predicting or monitoring treatment response.

In vivo [(123)I]CNS-1261 binding to D-serine-activated and MK801-blocked NMDA receptors: A storage phosphor imaging study in rats.

Disturbances of activity of the glutamatergic neurotransmitter system in the brain are present in many neuropsychiatric disorders. The N-methyl-D-aspartate (NMDA) receptor is the most abundant receptor of the glutamatergic system. In the neurodegenerative events of Alzheimer's disease, excessive activation of NMDA receptors may contribute to neuronal death. Inhibition of NMDA receptor activation may have neuroprotective effects and (semi)quantitative imaging of the activated system may help in the selection of patients for such inhibition therapies. In this study we evaluated [(123)I]CNS-1261 binding in the rat brain. This radiotracer binds in vivo to the MK801 binding site of activated NMDA receptors. To determine the optimal time point for ex vivo assessments after bolus injection [(123)I]CNS-1261 binding in rats, we performed a time course biodistribution study using dissection techniques. [(123)I]CNS-1261 binding was also studied in the rat brain using autoradiography by means of storage phosphor imaging, with prior facilitation of NMDA receptor activation by injection of the potent coagonist D-serine and after blocking of the NMDA receptor binding site by MK801 injection in D-serine pretreated rats. Measurements of [(123)I]CNS-1261 uptake matched the distribution of similar tracers for the MK801 binding site of the NMDA receptor and revealed an optimal time point of 2 h post injection for the assessment of tracer distribution in the rat brain. The blocking experiments indicated specific binding of [(123)I]CNS-1261 to NMDA receptors but also a considerable amount of nonspecific binding. Facilitation of NMDA receptor activation by D-serine did not result in an enhancement of binding of the radiotracer in the NMDA receptor-rich rat hippocampus compared to the untreated group, as measured by autoradiography. In conclusion, our study has shown that [(123)I]CNS-1261 binding is influenced by NMDA receptor availability. However, high nonspecific binding limits quantification and small changes in receptor availability are unlikely to be detected.

Localisation of regions of intense pleasure response evoked by soccer goals.

Localisation of regions of intense pleasure responses will lead to a better understanding of the reward mechanisms in the brain. Here we present a novel fMRI video paradigm designed to evoke high levels of pleasure in a specific test group and to distinguish regions of pleasure from anticipation. It exploits the intense commitment of soccer supporters and thus captures the intense euphoric feeling experienced when a soccer goal is scored. Nine healthy male subjects were imaged. Statistically significant activation clusters were determined for four contrasts: (i) goals vs. open play; (ii) missed chances vs. open play; (iii) goals vs. missed chances; and (iv) goals and missed chances vs. open play. Superior temporal, inferior frontal and amygdala were activated by all contrasts. Anterior cingulate cortex (ACC) was activated in contrasts (i) and (iii), suggesting that the ACC is involved in processing pleasure. The putamen was activated in contrasts (i), (ii) and (iv) implicating involvement of this region in the anticipation of pleasure. This paradigm activates brain regions known to be involved in pleasure-processing networks. The structure of the paradigm allows the separation of anticipation from the pleasure stimulus and provides a paradigm devoid of decision-making.

Rapid and efficient radiosynthesis of [123I]I-PK11195, a single photon emission computed tomography tracer for peripheral benzodiazepine receptors.

INTRODUCTION: [(123)I]I-PK11195 is a high-affinity single photon emission computed tomography radiotracer for peripheral benzodiazepine receptors that has previously been used to measure activated microglia and to assess neuroinflammation in the living human brain. This study investigates the radiosynthesis of [(123)I]I-PK11195 in order to develop a rapid and efficient method that obtains [(123)I]I-PK11195 with a high specific activity for in vivo animal and human imaging studies. METHODS: The synthesis of [(123)I]I-PK11195 was evaluated using a solid-state interhalogen exchange method and an electrophilic iododestannylation method, where bromine and trimethylstannyl derivatives were used as precursors, respectively. In the electrophilic iododestannylation method, the oxidants peracetic acid and chloramine-T were both investigated. RESULTS: Electrophilic iododestannylation produced [(123)I]I-PK11195 with a higher isolated radiochemical yield and a higher specific activity than achievable using the halogen exchange method investigated. Using chloramine-T as oxidant provided a rapid and efficient method of choice for the synthesis of [(123)I]I-PK11195. CONCLUSIONS: [(123)I]I-PK11195 has been successfully synthesized via a rapid and efficient electrophilic iododestannylation method, producing [(123)I]I-PK11195 with a higher isolated radiochemical yield and a higher specific activity than previously achieved.

Nicotinic alpha4beta2 receptor binding in dementia with Lewy bodies using 123I-5IA-85380 SPECT demonstrates a link between occipital changes and visual hallucinations.

INTRODUCTION: To investigate in vivo differences in the distribution of alpha4beta2 subtypes of nAChR using the ligand (123)I-5-Iodo-3-[2(S)-2-azetidinylmethoxy] pyridine (5IA-85380) and single photon emission computed tomography (SPECT) in DLB and similarly aged controls. METHODS: Thirty-one subjects (15 DLB and 16 controls) underwent (123)I-5IA-85380 and perfusion ((99m)Tc-exametazime) SPECT scanning. Patient scans were compared to scans of control subjects on a voxel-by-voxel basis using SPM2. RESULTS: Compared to controls, significant reductions in relative (123)I-5IA-85380 uptake were identified in frontal, striatal, temporal and cingulate regions in DLB. Elevation of scaled (123)I-5IA-85380 uptake in occipital cortex was observed in DLB relative to controls, as well as being associated with DLB subjects with a recent history of visual hallucinations. Changes in (123)I-5IA-85380 SPECT in DLB were different from perfusion. CONCLUSION: Reductions in normalised (123)I-5IA-85380 uptake in DLB were distinct from their perfusion deficits. Significant increase in occipital lobe uptake was present in DLB, a change most pronounced in subjects with a recent history of visual hallucinations. The findings directly link cholinergic changes in occipital lobe to visual hallucinations in DLB.

alpha4beta2-nicotinic receptor binding with 5-IA in Alzheimer's disease: methods of scan analysis.

Five patients with Alzheimer's disease and five healthy volunteers were examined by SPECT with the nicotinic receptor ligand 123I-5-IA-85380. Patients were scanned before and after 6 weeks of treatment with donepezil. Quantification by regions of interest was reliable and the optimal normalisation procedure used cerebellar ratios. We found relative reductions in 5-IA binding capacity in patients in thalamus, frontal and central regions of interest of approximately one standard deviation unit (Cohen's d = 1). Reductions in binding after treatment with the acetylcholinesterase inhibitor donepezil of the same magnitude occurred in the brain stem. The study was clearly too small to confirm group differences, but it suggests that 5-IA can be used to examine both group differences and treatment effects in patients with Alzheimer's disease.

Muscarinic acetylcholine receptor status in Alzheimer's disease assessed using (R, R) 123I-QNB SPECT.

BACKGROUND: One of the most characteristic changes in Alzheimer's disease (AD) is a deficit in cortical cholinergic neurotransmission and associated receptor changes. OBJECTIVE: To investigate differences in the distribution of M1/M4 receptors using (R, R) (123)I-iodo-quinuclidinyl-benzilate (QNB) and single photon emission computed tomography (SPECT) in patients with mild/moderate AD and age-matched controls. Also, to compare (123)I-QNB uptake to the corresponding changes in regional cerebral blood flow (rCBF) in the same subjects. METHODS: Forty two subjects (18 AD and 24 healthy elderly controls) underwent (123)IQNB and perfusion (99m)Tc-exametazime SPECT scanning. Image analysis was performed using statistical parametric mapping (SPM99) following intensity normalisation of each image to its corresponding mean whole brain uptake. Group differences and correlations were assessed using two sample t-tests and linear regression respectively. RESULTS: Significant reductions in (123)I-QNB uptake were observed in regions of the frontal rectal gyrus, right parahippocampal gyrus, left hippocampus and areas of the left temporal lobe in AD compared to controls (height threshold of p < or = 0.001 uncorrected). Such regions were also associated with marked deficits in rCBF. No significant correlations were identified between imaging data and clinical variables. CONCLUSION: Functional impairment as measured by rCBF is more widespread than changes in M1/M4 receptor density in mild/moderate AD, where there was little or no selective loss of M1/M4 receptors in these patients that was greater than the general functional deficits shown on rCBF scans.

In vivo SPECT imaging of muscarinic acetylcholine receptors using (R,R) 123I-QNB in dementia with Lewy bodies and Parkinson's disease dementia.

INTRODUCTION: Alterations in cholinergic function have been reported to be associated with dementia. The aim of this study was to investigate differences in the distribution of muscarinic acetylcholine receptors (mAChRs) using (R,R) 123I-iodo-quinuclidinyl-benzilate (QNB) and single photon emission computed tomography (SPECT) in dementia with Lewy bodies (DLB), Parkinson's disease dementia (PDD) and age-matched controls. 123I-QNB binding was also compared to the corresponding cerebral perfusion changes in the same subjects. METHODS: 63 subjects (24 controls, 14 DLB, 25 PDD) underwent 123I-QNB and perfusion 99mTc-exametazine SPECT scanning. Image analysis, using statistical parametric mapping (SPM99), involved spatial normalisation of each image to a customised template, followed by smoothing and intensity normalisation of each image to its corresponding mean whole brain uptake. Group effects and correlations were assessed using two sample t tests and linear regression respectively. RESULTS: Relative to controls, significant elevation of 123I-QNB binding was apparent in the right occipital lobe in DLB and right and left occipital lobes in PDD (height threshold p

Assessment of 123I-FIAU imaging of herpes simplex viral gene expression in the treatment of glioma.

BACKGROUND: Herpes simplex virus 1716 (HSV1716), a selectively replication competent mutant of HSV1, is under investigation as an oncolytic viral therapy in human malignant glioma. As with similar therapies, a technique for measurement of viral replication and distribution over time following virus administration is required. Imaging expression of the HSV-thymidine kinase (HSV-tk) gene offers an opportunity for non-invasive assessment of viral distribution in living subjects. This is the first study to explore the use of HSV-tk as a reporter gene and radiolabelled thymidine analogue 5-[(123)I]iodo-1-(2-deoxy-2-fluoro-beta-D-arabinofuranosyl) uracil ((123)I-FIAU) as a marker substrate to non-invasively monitor HSV1716 replication in humans during treatment of high-grade glioma. METHODS: I-FIAU brain SPECT imaging was undertaken in eight patients receiving intra-tumoural injection of HSV1716, before and after administration of the virus. Baseline images were acquired 3 days prior to virus administration and between 1 and 5 days following virus administration. Region of interest analysis was used to investigate whether there was an increase in (123)I-FIAU concentration following virus administration due to HSV-tk expression. RESULT: Increased (123)I-FIAU accumulation due to HSV-tk expression was not detected in this study. The possible explanations for this finding are explored and design options for future studies are discussed.

Thalamic nicotinic receptors implicated in disturbed consciousness in dementia with Lewy bodies.

Disturbances of consciousness (DOC) are common in dementia with Lewy bodies (DLB). Following previous findings of preserved temporal cortical high-affinity nicotinic binding relating to DOC, we investigated this receptor in thalamus, an area of high nicotinic receptor concentration, implicated in consciousness. 5-[125I]-A-85380 binding, primarily reflecting the alpha4beta2 subtype, was compared in 16 DLB patients with DOC and 6 without DOC, matched for duration and severity of dementia. Binding was higher in patients with DOC compared to patients without DOC in all thalamic nuclei examined, reaching significance in the reticular and ventral anterior thalamic nuclei. Comparing DLB patients with and without DOC to previously reported controls revealed similar binding levels in patients with DOC and lower binding in patients without DOC, reaching significance in the ventral anterior, indicating preserved nicotinic receptor density in DLB patients with DOC. These findings, together with previous neocortical data, implicate nicotinic modulation of thalamo-cortical circuitry as a key component in the control of conscious awareness in DLB.

Serotonin transporter residual availability during long-term antidepressant therapy does not differentiate responder and nonresponder unipolar patients.

BACKGROUND: Serotonin transporters (SERT) are a major target for antidepressant medication, although there have been limited in vivo studies of SERT availability in patients being treated with antidepressants. It is not known whether SERT availability differs in treatment-responsive and -nonresponsive patients receiving long-term treatment. In this study, we used single photon emission computed tomography (SPECT) to compare SERT residual availability in unipolar responders and nonresponders during long-term antidepressant treatment. Dopamine transporter (DAT) availability was also assessed in the same patients to examine the relationship between the two transporter systems. METHODS: Twenty-four medicated unipolar patients were recruited, of whom 11 were responders and 13 were nonresponders. All patients underwent SPECT with [123I] beta-carbomethoxy-3-beta-(4 iodophenyl)tropane. Brain SERT was measured in the brain stem and diencephalon, and DAT was measured in the striatum. Residual availability was calculated as a ratio of specific to nonspecific uptake, with the occipital region used as the nonspecific reference region. RESULTS: There was no difference between responders and nonresponders in SERT availability. Dopamine transporter availability was similar in responders and nonresponders, and there was no association between SERT and DAT availability. CONCLUSIONS: Serotonin transporter availability does not discriminate responders and nonresponders during long-term treatment with antidepressants.

Perfusion SPECT in cochlear implantation and promontory stimulation.

BACKGROUND: Recent studies of profoundly deaf patients with cochlear implants have demonstrated that these patients are able to process sound in the auditory cortex in a similar way to normal subjects. However, there are large variations in outcome. Various clinical criteria are used for subject selection and the decision as to which ear is to be implanted involves electrical stimulation of the promontory which is used to confirm the persistence of auditory neurones and fibres that can be utilized by the cochlear implant. In this study we have used SPECT with Tc-HMPAO to investigate activation of the auditory cortex in cochlear implantees post-surgery. In addition we also investigated whether electrical stimulation of the promontory does produce change in blood flow in the auditory cortex in pre-surgery candidates, which would indicate viable auditory networks that can be utilized by a cochlear implant device. METHODS AND RESULTS: Image analysis was performed with SPM99. Results of a simple subtraction paradigm indicated bilateral activation of auditory cortex and Wernicke's area in the post-implant group during auditory stimulus (speech) and bilateral activation of the ventral lateral posterior thalamus and bilateral auditory association cortex BA21/22/42, in the pre-implant group during electrical stimulus but no activation of the primary auditory cortex. A conjunction analysis used to investigate the common areas of activation across both groups during the stimulus condition showed that there was a common bilateral activation of the primary auditory cortex in both groups (BA22/41/42). In addition, analysis of a subset of the seven post-implant subjects who did not comprehend the speech in our study showed an activation (Pu<0.05, where Pu is the peak voxel threshold, uncorrected for multiple comparisons) in the left auditory cortex that extended into area BA22 synonymous with Wernicke's area. This supports the theory that this region has a sensory role.