D J Brooks

Publications of D J Brooks

• Cerebral microglial activation in patients with hepatitis c: in vivo evidence of neuroinflammation.

  Authors: V P B Grover, N Pavese, S-B Koh, M Wylezinska, B K Saxby, A Gerhard, D M Forton, D J Brooks, H C Thomas, S D Taylor-Robinson

  Journal of viral hepatitis. 02/2012; 19(2):e89-96.

  Patients with chronic hepatitis C infection may exhibit neuropsychological symptoms and cognitive impairment. Post-mortem studies of hepatitis C virus HCV quasispecies and replicative intermediatesPatients with chronic hepatitis C infection may exhibit neuropsychological symptoms and cognitive impairment. Post-mortem studies of hepatitis C virus HCV quasispecies and replicative intermediates indicate that the brain might act as a separate compartment for viral replication and microglia may be the locus for infection and subsequent neuroinflammatory activity. We sought to use two independent in vivo imaging techniques to determine evidence of neuroinflammation in patients with histologically mild chronic hepatitis C. Using positron emission tomography (PET) with a ligand for microglial/brain macrophage activation, (11)C-(R)-PK11195 (PK11195) and cerebral proton magnetic resonance spectroscopy, we determined whether there was evidence of neuroinflammation in a pilot study of 11 patients with biopsy-proven mild chronic hepatitis C, compared to healthy volunteers. Patients were characterized by cognitive testing and the fatigue impact scale to assess for CNS impairment. PK11195 binding potential was significantly increased in the caudate nucleus of patients, compared to normal controls (P = 0.03). The caudate and thalamic binding potential were more significantly increased in six patients with genotype 1 infection (P = 0.007) and positively correlated with viraemia (r = 0.77, P = 0.005). Basal ganglia myo-inositol/creatine and choline/creatine ratios were also significantly elevated in patients with chronic hepatitis C compared to normal controls (P = 0.0004 and P = 0.01, respectively). Using PET, we demonstrated evidence of microglial activation, which positively correlated with HCV viraemia and altered cerebral metabolism in the brains of patients with mild hepatitis C. This provides further in vivo evidence for a neurotropic role for HCV.

• Can target-to-pons ratio be used as a reliable method for the analysis of [(11)C]PIB brain scans?

  Authors: P Edison, R Hinz, A Ramlackhansingh, J Thomas, G Gelosa, H A Archer, F E Turkheimer, D J Brooks

  NeuroImage. 01/2012; 60(3):1716-23.

  (11)C]PIB is the most widely used PET imaging marker for amyloid in dementia studies. In the majority of studies the cerebellum has been used as a reference region. However, cerebellar amyloid may be(11)C]PIB is the most widely used PET imaging marker for amyloid in dementia studies. In the majority of studies the cerebellum has been used as a reference region. However, cerebellar amyloid may be present in genetic Alzheimer's (AD), cerebral amyloid angiopathy and prion diseases. Therefore, we investigated whether the pons could be used as an alternative reference region for the analysis of [(11)C]PIB binding in AD. The aims of the study were to: 1) Evaluate the pons as a reference region using arterial plasma input function and Logan graphical analysis of binding. 2) Assess the power of target-to-pons ratios to discriminate controls from AD subjects. 3) Determine the test-retest reliability in AD subjects. 4) Demonstrate the application of target-to-pons ratio in subjects with elevated cerebellar [(11)C]PIB binding. 12 sporadic AD subjects aged 65±4.5yrs with a mean MMSE 21.4±4 and 10 age-matched control subjects had [(11)C]PIB PET with arterial blood sampling. Three additional subjects (two subjects with pre-symptomatic presenilin-1 mutation carriers and one probable familial AD) were also studied. Object maps were created by segmenting individual MRIs and spatially transforming the gray matter images into standard stereotaxic MNI space and then superimposing a probabilistic atlas. Cortical [(11)C]PIB binding was assessed with an ROI (region of interest) analysis. Parametric maps of the volume of distribution (V(T)) were generated with Logan analysis. Additionally, parametric maps of the 60-90min target-to-cerebellar ratio (RATIO(CER)) and the 60-90min target-to-pons ratio (RATIO(PONS)) were computed. All three approaches were able to differentiate AD from controls (p<0.0001, nonparametric Wilcoxon rank sum test) in the target regions with RATIO(CER) and RATIO(PONS) differences higher than V(T) with use of an arterial input function. All methods had a good reproducibility (intraclass correlation coefficient>0.83); RATIO(CER) performed best closely followed by RATIO(PONS). The two subjects with presenilin-1 mutations and the probable familial AD case showed no significant differences in cortical binding using RATIO(CER), but the RATIO(PONS) approach revealed higher [(11)C]PIB binding in cortex and cerebellum. This study established 60-90min target-to-pons RATIOs as a reliable method of analysis in [(11)C]PIB PET studies where cerebellum is not an appropriate reference region.

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  Authors: N. Pavese, B. S. Simpson, V. Metta, A. Ramlackhansingh, K. Ray Chaudhuri, D. J. Brooks

  NeuroImage. 01/2012; 59:1080-1084.

• [¹⁸F]FDOPA uptake in the raphe nuclei complex reflects serotonin transporter availability. A combined [¹⁸F]FDOPA and [¹¹C]DASB PET study in Parkinson's disease.

  Authors: N Pavese, B S Simpson, V Metta, A Ramlackhansingh, K Ray Chaudhuri, D J Brooks

  NeuroImage. 09/2011; 59(2):1080-4.

  Brain uptake of [(18)F]FDOPA, measured with PET, reflects the activity of aromatic amino acid decarboxylase, an enzyme largely expressed in monoaminergic nerve terminals. This enzyme catalyzes aBrain uptake of [(18)F]FDOPA, measured with PET, reflects the activity of aromatic amino acid decarboxylase, an enzyme largely expressed in monoaminergic nerve terminals. This enzyme catalyzes a number of decarboxylation reactions including conversion of l-dopa into dopamine and 5-hydroxytryptophan into serotonin. For more than 20years [(18)F]FDOPA PET has been used to assess dopaminergic nigrostriatal dysfunction in patients with Parkinson's disease (PD). More recently, however, [(18)F]FDOPA PET has also been employed as a marker of serotoninergic and noradrenergic function in PD patients. In this study, we provide further evidence in support of the view that [(18)F]FDOPA PET can be used to evaluate the distribution and the function of serotoninergic systems in the brain. Eighteen patients with PD were investigated with both [(18)F]FDOPA and [(11)C]DASB PET, the latter being a marker of serotonin transport (SERT) availability. We then assessed the relationship between measurements of the two tracers within brain serotoninergic structures. [(18)F]FDOPA uptake in the median raphe nuclei complex of PD patients was significantly correlated with SERT availability in the same structure. Trends towards significant correlations between [(18)F]FDOPA Ki values and [(11)C]DASB binding values were also observed in the hypothalamus and the anterior cingulate cortex, suggesting a serotoninergic contribution to [(18)F]FDOPA uptake in these regions. Conversely, no correlations were found in brain structures with mixed dopaminergic, serotoninergic and noradrenergic innervations, or with predominant dopaminergic innervation. These findings provide evidence that [(18)F]FDOPA PET represents a valid marker of raphe serotoninergic function in PD and supports previous studies where [(18)F]FDOPA PET has been used to assess serotoninergic function in PD.

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

  Authors: A F Ramlackhansingh, S K Bose, I Ahmed, F E Turkheimer, N Pavese, D J Brooks

  Neurology. 05/2011; 76(21):1811-6.

  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 theTo 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. 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 (V(T)) were computed for the caudate, putamen, and thalamus and binding potentials (BP(ND)) reflecting the ratio of specific:nonspecific uptake were compared between groups. 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. 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.

• PATH51 Investigating adenosine A2A receptor availability in Parkinson's disease patients with and without levodopa induced dyskinesias with [11C]SCH442416 PET.

  Authors: A Ramlackhansingh, S K Bose, I Ahmed, N Pavese, D J Brooks, F E Turkheimer

  Journal of neurology, neurosurgery, and psychiatry. 11/2010; 81(11):e21.

  Objective To investigate adenosine 2A (A2A) receptor availability in Parkinson's disease (PD) patients with and without levodopa induced dyskinesias (LID). Background Levodopa use is key to treatmentObjective To investigate adenosine 2A (A2A) receptor availability in Parkinson's disease (PD) patients with and without levodopa induced dyskinesias (LID). Background Levodopa use is key to treatment in PD. Its use is associated with the development of LID. Adenosine regulates dopamine release so dyskinesias may be related to changes in striatal A2A availability. We have studied A2A receptor availability in PD patients with and without LID using [11C]SCH442416 PET, a marker of A2A receptor function. Design/methods Six PD patients with LID and six without LID were studied withdrawn from medications. Results were compared with three age matched controls. Using spectral analysis, [11C]SCH442416 regional volumes of distribution were computed. Striatal and thalamic binding potentials (BP) reflecting the ratio of specific:nonspecific uptake were compared between groups. Results Striatal A2A binding of PD subjects with LID was significantly raised (p=0.017). This was also reflected in striatal subdivisions. Thalamic BP was similar between all PD subjects. The striatal BPs of controls lay within the BP range of the PD subjects without LID. Conclusion PD patients with LID show increased striatal A2A receptor availability. This provides a rationale for using A2A receptor antagonists in the management of dyskinesias.

• Depressive symptoms in PD correlate with higher 5-HTT binding in raphe and limbic structures.

  Authors: M Politis, K Wu, C Loane, F E Turkheimer, S Molloy, D J Brooks, P Piccini

  Neurology. 11/2010; 75(21):1920-7.

  Depression associated with Parkinson disease (PD) has a different symptom profile to endogenous depression. The etiology of depression in PD remains uncertain though abnormal serotonergicDepression associated with Parkinson disease (PD) has a different symptom profile to endogenous depression. The etiology of depression in PD remains uncertain though abnormal serotonergic neurotransmission could play a role. To assess with PET serotonergic function via in vivo serotonin transporter (5-HTT) availability in antidepressant-naive patients with PD. Thirty-four patients with PD and 10 healthy matched control subjects had a clinical battery of tests including the patient-report Beck Depression Inventory-II (BDI-II), the clinician-report Hamilton Rating Scale for Depression (HRSD), and the structured clinical interview for DSM-IV Axis I Disorders (SCID-I). They underwent ¹¹C-DASB PET, a selective in vivo marker of 5-HTT binding in humans. BDI-II scores correlated with HRSD scores. Ten of 34 patients with PD (29.4%) had BDI-II and HRSD scores above the discriminative cutoff for PD depression though only half of these patients could be classed on SCID-I criteria as having an anxiety/mood disorder. Patients with PD with the highest scores for depression symptoms showed significantly raised ¹¹C-DASB binding in amygdala, hypothalamus, caudal raphe nuclei, and posterior cingulate cortex compared to low score cases, while ¹¹C-DASB binding values in other regions were similarly decreased in depressed and nondepressed patients with PD compared to healthy controls. Depressive symptoms in antidepressant-naive patients with PD correlate with relatively higher 5-HTT binding in raphe nuclei and limbic structures possibly reflecting lower extracellular serotonin levels. Our data are compatible with a key role of abnormal serotonergic neurotransmission contributing to the pathophysiology of PD depression and justify the use of agents acting on 5-HTT.

• Serotonergic neurons mediate dyskinesia side effects in Parkinson's patients with neural transplants

  Authors: M. Politis, K. Wu, C. Loane, N.P. Quinn, D.J. Brooks, S. Rehncrona, A. Bjorklund, O. Lindvall, P. Piccini

  Sci.Transl.Med. 06/2010; 2(38).

  Troublesome involuntary movements in the absence of dopaminergic medication, so-called off-medication dyskinesias, are a serious adverse effect of fetal neural grafts that hinders the development ofTroublesome involuntary movements in the absence of dopaminergic medication, so-called off-medication dyskinesias, are a serious adverse effect of fetal neural grafts that hinders the development of cell-based therapies for Parkinson's disease. The mechanisms underlying these dyskinesias are not well understood, and it is not known whether they are the same as in the dyskinesias induced by l-dopa treatment. Using in vivo brain imaging, we show excessive serotonergic innervation in the grafted striatum of two patients with Parkinson's disease, who had exhibited major motor recovery after transplantation with dopamine-rich fetal mesencephalic tissue but had later developed off-medication dyskinesias. The dyskinesias were markedly attenuated by systemic administration of a serotonin [5-hydroxytryptamine (5-HT)] receptor (5-HT(1A)) agonist, which dampens transmitter release from serotonergic neurons, indicating that the dyskinesias were caused by the serotonergic hyperinnervation. Our observations suggest strategies for avoiding and treating graft-induced dyskinesias that result from cell therapies for Parkinson's disease with fetal tissue or stem cells

• (11)C-PIB PET in subjective cognitive impairment.

  Authors: J Rodda, A Okello, P Edison, T Dannhauser, D J Brooks, Z Walker

  European psychiatry : the journal of the Association of European Psychiatrists. 11/2009;

  People with Subjective Cognitive Impairment (SCI) may be at increased risk of dementia. In this study we examined amyloid load in 5 SCI subjects and 14 controls using PIB PET scanning. One SCIPeople with Subjective Cognitive Impairment (SCI) may be at increased risk of dementia. In this study we examined amyloid load in 5 SCI subjects and 14 controls using PIB PET scanning. One SCI subject had significantly increased PIB retention in the cortical areas of interest. Larger, longitudinal studies are indicated.

• Conversion of amyloid positive and negative MCI to AD over 3 years. An 11C-PIB PET study.

  Authors: A Okello, J Koivunen, P Edison, H A Archer, F E Turkheimer, K Någren, R Bullock, Z Walker, A Kennedy, N C Fox, M N Rossor, J O Rinne, D J Brooks

  Neurology. 08/2009;

  BACKGROUND: Patients with amnestic mild cognitive impairment (MCI) represent an important clinical group as they are at increased risk of developing Alzheimer disease (AD). (11)C-PIB PET is an inBACKGROUND: Patients with amnestic mild cognitive impairment (MCI) represent an important clinical group as they are at increased risk of developing Alzheimer disease (AD). (11)C-PIB PET is an in vivo marker of brain amyloid load. OBJECTIVE: To assess the rates of conversion of MCI to AD during a 3-year follow-up period and to compare levels of amyloid deposition between MCI converters and nonconverters. METHODS: Thirty-one subjects with MCI with baseline (11)C-PIB PET, MRI, and neuropsychometry have been clinically followed up for 1 to 3 years (2.68 +/- 0.6 years). Raised cortical (11)C-PIB binding in subjects with MCI was detected with region of interest analysis and statistical parametric mapping. RESULTS: Seventeen of 31 (55%) subjects with MCI had increased (11)C-PIB retention at baseline and 14 of these 17 (82%) clinically converted to AD during follow-up. Only one of the 14 PIB-negative MCI cases converted to AD. Of the PIB-positive subjects with MCI, half (47%) converted to AD within 1 year of baseline PIB PET, these faster converters having higher tracer-retention values than slower converters in the anterior cingulate (p = 0.027) and frontal cortex (p = 0.031). Seven of 17 (41%) subjects with MCI with known APOE status were epsilon4 allele carriers, this genotype being associated with faster conversion rates in PIB-positive subjects with MCI (p = 0.035). CONCLUSIONS: PIB-positive subjects with mild cognitive impairment (MCI) are significantly more likely to convert to AD than PIB-negative patients, faster converters having higher PIB retention levels at baseline than slower converters. In vivo detection of amyloid deposition in MCI with PIB PET provides useful prognostic information.

• Microglial activation and amyloid deposition in mild cognitive impairment: a PET study.

  Authors: A Okello, P Edison, H A Archer, F E Turkheimer, J Kennedy, R Bullock, Z Walker, A Kennedy, N Fox, M Rossor, D J Brooks

  Neurology. 01/2009; 72(1):56-62.

  BACKGROUND: Activated microglia may play a role in the pathogenesis of Alzheimer disease (AD) as they cluster around beta-amyloid (Abeta) plaques. They are, therefore, a potential therapeutic targetBACKGROUND: Activated microglia may play a role in the pathogenesis of Alzheimer disease (AD) as they cluster around beta-amyloid (Abeta) plaques. They are, therefore, a potential therapeutic target in both AD and its prodrome amnestic mild cognitive impairment (MCI). OBJECTIVE: To characterize in vivo with (11)C-(R)-PK11195 and (11)C-PIB PET the distribution of microglial activation and amyloid deposition in patients with amnestic MCI. METHODS: Fourteen subjects with MCI had (11)C-(R)-PK11195 and (11)C-PIB PET with psychometric tests. RESULTS: Seven out of 14 (50%) patients with MCI had increased cortical (11)C-PIB retention (p < 0.001) while 5 out of 13 (38%) subjects with MCI showed increased (11)C-(R)-PK11195 uptake. The MCI subgroup with increased (11)C-PIB retention also showed increased cortical (11)C-(R)-PK11195 binding (p < 0.036) though this increase only remained significant in frontal cortex after a correction for multiple comparisons. There was no correlation between regional levels of (11)C-(R)-PK11195 and (11)C-PIB binding in individual patients with MCI: only three of the five MCI cases with increased (11)C-(R)-PK11195 binding had increased levels of (11)C-PIB retention. CONCLUSIONS: Our findings indicate that, while amyloid deposition and microglial activation can be detected in vivo in around 50% of patients with mild cognitive impairment (MCI), these pathologies can occur independently. The detection of microglial activation in patients with MCI suggests that anti-inflammatory therapies may be relevant to the prevention of AD.

• Amyloid load in Parkinson's disease dementia and Lewy body dementia measured with [11C]PIB positron emission tomography.

  Authors: P Edison, C C Rowe, J O Rinne, S Ng, I Ahmed, N Kemppainen, V L Villemagne, G O'Keefe, K Någren, K R Chaudhury, C L Masters, D J Brooks

  Journal of neurology, neurosurgery, and psychiatry. 12/2008; 79(12):1331-8.

  Neuropathological studies have reported varying amounts of amyloid pathology in dementia with Lewy bodies (DLB) and Parkinson's disease dementia (PDD). [11C]PIB positron emission tomography (PET) isNeuropathological studies have reported varying amounts of amyloid pathology in dementia with Lewy bodies (DLB) and Parkinson's disease dementia (PDD). [11C]PIB positron emission tomography (PET) is a marker of brain amyloid deposition. The aim of this study was to quantify in vivo amyloid load in DLB and PDD compared with control subjects and subjects with Parkinson's disease (PD) without dementia. 13 DLB, 12 PDD, 10 PD subjects and 41 age matched controls (55-82 years) were recruited. Each subject underwent clinical evaluation, neuropsychological assessment, T1 and T2 MRI, and [11C]PIB PET. The amyloid load was estimated from 60-90' target region:cerebellar [11C]PIB uptake ratios. Object maps were created by segmenting individual MRIs and convolving them with a probabilistic atlas. Cortical [11C]PIB uptake was assessed by region of interest analysis. The DLB cohort showed a significant increase in mean brain [11C]PIB uptake and individually 11 of the 13 subjects with DLB had a significantly increased amyloid load. In contrast, mean [11C]PIB uptake was normal for the PDD group although two of 12 patients with PDD individually showed a raised amyloid load. Where significant increases in [11C]PIB uptake were found, it was increased in cortical association areas, cingulate and striatum. None of the subjects with PD showed significantly raised cortical [11C]PIB uptake. This study suggests that amyloid load is significantly raised in over 80% of subjects with DLB, while amyloid pathology is infrequent in PDD. These in vivo PET findings suggest that the presence of amyloid in DLB could contribute to the rapid progression of dementia in this condition and that anti-amyloid strategies may be relevant.

• Positron emission tomography analysis of [(11)C]KW-6002 binding to human and rat adenosine A(2A) receptors in the brain.

  Authors: D J Brooks, M Doder, S Osman, S K Luthra, E Hirani, S Hume, H Kase, J Kilborn, S Martindill, A Mori

  Synapse (New York, N.Y.). 10/2008; 62(9):671-81.

  Adenosine A(2A) receptors are found on striatal neurones projecting to the external pallidum. KW-6002 (istradefylline) is a potent and selective antagonist for the adenosine A(2A) receptors in theAdenosine A(2A) receptors are found on striatal neurones projecting to the external pallidum. KW-6002 (istradefylline) is a potent and selective antagonist for the adenosine A(2A) receptors in the CNS and acts to inhibit the excessive activity of this pathway in the MPTP marmoset model of PD, thus relieving parkinsonism. The objectives of this study were to investigate the regional binding of the novel positron emission tomography tracer [(11)C]KW-6002 in the healthy human brain and the rat brain, along with receptor occupancy by cold KW-6002 at varying doses in human. The highest [(11)C]KW-6002 uptake in the rat brain was seen in striatum and lower levels in cortex and cerebellum. Brain [(11)C]KW-6002 uptake was well characterized in humans by a two-tissue compartmental model with a blood volume term, and the ED(50) of cold KW-6002 was 0.5 mg in the striatum. Over 90% receptor occupancy was achieved with daily oral doses of greater than 5 mg. In humans, blockable binding was present in all gray matter structures including the cerebellum, which has not been reported to express A(2A) receptors. MRS 1745, an A(2B) receptor selective antagonist, had no effect on the cerebellar binding of [(11)C]KW-6002 in rats, suggesting that this blockable signal is unlikely to result from an affinity for adenosine A(2B) receptors. Synapse 62:671-681, 2008. (c) 2008 Wiley-Liss, Inc.

• Long-term clinical and positron emission tomography outcome of fetal striatal transplantation in Huntington's disease.

  Authors: I Reuter, Y F Tai, N Pavese, K R Chaudhuri, S Mason, C E Polkey, C Clough, D J Brooks, R A Barker, P Piccini

  Journal of neurology, neurosurgery, and psychiatry. 09/2008; 79(8):948-51.

  Two patients with moderate Huntington's disease (HD) received bilateral fetal striatal allografts. One patient demonstrated, for the first time, increased striatal D2 receptor binding, evident withTwo patients with moderate Huntington's disease (HD) received bilateral fetal striatal allografts. One patient demonstrated, for the first time, increased striatal D2 receptor binding, evident with 11C-raclopride positron emission tomography, and prolonged clinical improvement over 5 years, suggesting long term survival and efficacy of the graft. The other patient did not improve clinically or radiologically. Our results indicate that striatal transplantation in HD may be beneficial but further studies are needed to confirm this.

• Second consensus statement on the diagnosis of multiple system atrophy.

  Authors: S Gilman, G K Wenning, P A Low, D J Brooks, C J Mathias, J Q Trojanowski, N W Wood, C Colosimo, A Dürr, C J Fowler, H Kaufmann, T Klockgether, A Lees, W Poewe, N Quinn, T Revesz, D Robertson, P Sandroni, K Seppi, M Vidailhet

  Neurology. 09/2008; 71(9):670-6.

  BACKGROUND: A consensus conference on multiple system atrophy (MSA) in 1998 established criteria for diagnosis that have been accepted widely. Since then, clinical, laboratory, neuropathologic, andBACKGROUND: A consensus conference on multiple system atrophy (MSA) in 1998 established criteria for diagnosis that have been accepted widely. Since then, clinical, laboratory, neuropathologic, and imaging studies have advanced the field, requiring a fresh evaluation of diagnostic criteria. We held a second consensus conference in 2007 and present the results here. METHODS: Experts in the clinical, neuropathologic, and imaging aspects of MSA were invited to participate in a 2-day consensus conference. Participants were divided into five groups, consisting of specialists in the parkinsonian, cerebellar, autonomic, neuropathologic, and imaging aspects of the disorder. Each group independently wrote diagnostic criteria for its area of expertise in advance of the meeting. These criteria were discussed and reconciled during the meeting using consensus methodology. RESULTS: The new criteria retain the diagnostic categories of MSA with predominant parkinsonism and MSA with predominant cerebellar ataxia to designate the predominant motor features and also retain the designations of definite, probable, and possible MSA. Definite MSA requires neuropathologic demonstration of CNS alpha-synuclein-positive glial cytoplasmic inclusions with neurodegenerative changes in striatonigral or olivopontocerebellar structures. Probable MSA requires a sporadic, progressive adult-onset disorder including rigorously defined autonomic failure and poorly levodopa-responsive parkinsonism or cerebellar ataxia. Possible MSA requires a sporadic, progressive adult-onset disease including parkinsonism or cerebellar ataxia and at least one feature suggesting autonomic dysfunction plus one other feature that may be a clinical or a neuroimaging abnormality. CONCLUSIONS: These new criteria have simplified the previous criteria, have incorporated current knowledge, and are expected to enhance future assessments of the disease.

• Cortical 5-HT1A receptor binding in patients with homozygous D90A SOD1 vs sporadic ALS.

  Authors: M R Turner, E A Rabiner, A Al-Chalabi, C E Shaw, D J Brooks, P N Leigh, P M Andersen

  Neurology. 05/2007; 68(15):1233-5.

• Characterization of dopaminergic dysfunction in familial progressive supranuclear palsy: an 18F-dopa PET study.

  Authors: Y F Tai, R L Ahsan, J G de Yébenes, N Pavese, D J Brooks, P Piccini

  Journal of neural transmission (Vienna, Austria : 1996). 04/2007; 114(3):337-40.

  We analyzed (18)F-dopa PET data from 11 members of kindreds with familial progressive supranuclear palsy (PSP) to characterize their cerebral dopaminergic dysfunction. Three clinically-affected PSPWe analyzed (18)F-dopa PET data from 11 members of kindreds with familial progressive supranuclear palsy (PSP) to characterize their cerebral dopaminergic dysfunction. Three clinically-affected PSP patients showed reduced (18)F-dopa uptake in the striatum, orbitofrontal cortex and amygdala. One asymptomatic subject exhibited progressive putamen dopaminergic dysfunction. 60% of subjects with abnormal (18)F-dopa scans developed PSP subsequently. This is the first in vivo documentation of cortical dopaminergic deficiency in PSP. Reduced striatal (18)F-dopa uptake in susceptible relatives may predict later clinical disease.

• Amyloid, hypometabolism, and cognition in Alzheimer disease: an [11C]PIB and [18F]FDG PET study.

  Authors: P Edison, H A Archer, R Hinz, A Hammers, N Pavese, Y F Tai, G Hotton, D Cutler, N Fox, A Kennedy, M Rossor, D J Brooks

  Neurology. 03/2007; 68(7):501-8.

  OBJECTIVE: To investigate the association between brain amyloid load in Alzheimer disease (AD) measured by [11C]PIB-PET, regional cerebral glucose metabolism (rCMRGlc) measured by [18F]FDG-PET, andOBJECTIVE: To investigate the association between brain amyloid load in Alzheimer disease (AD) measured by [11C]PIB-PET, regional cerebral glucose metabolism (rCMRGlc) measured by [18F]FDG-PET, and cognition. METHODS: Nineteen subjects with AD and 14 controls had [11C]PIB-PET and underwent a battery of psychometric tests. Twelve of those subjects with AD and eight controls had [18F]FDG-PET. Parametric images of [11C]PIB binding and rCMRGlc were interrogated with a region-of-interest atlas and statistical parametric mapping. [11C]PIB binding and rCMRGlc were correlated with scores on psychometric tests. RESULTS: AD subjects showed twofold increases in mean [11C]PIB binding in cingulate, frontal, temporal, parietal, and occipital cortical areas. Higher cortical amyloid load correlated with lower scores on facial and word recognition tests. Two patients fulfilling the clinical criteria for AD had normal [11C]PIB at baseline. Over 20 months this remained normal in one but increased in the cingulate of the other. Mean levels of temporal and parietal rCMRGlc were reduced by 20% in AD and these correlated with mini mental scores, immediate recall, and recognition memory test for words. Higher [11C]PIB uptake correlated with lower rCMRGlc in temporal and parietal cortices. CONCLUSION: [11C]PIB-PET detected an increased amyloid plaque load in 89% of patients with clinically probable Alzheimer disease (AD). The high frontal amyloid load detected by [11C]PIB-PET in AD in the face of spared glucose metabolism is of interest and suggests that amyloid plaque formation may not be directly responsible for neuronal dysfunction in this disorder.

• Clinical correlates of levodopa-induced dopamine release in Parkinson disease: a PET study.

  Authors: N Pavese, A H Evans, Y F Tai, G Hotton, D J Brooks, A J Lees, P Piccini

  Neurology. 12/2006; 67(9):1612-7.

  OBJECTIVE: To evaluate the relationship between clinical improvement and in vivo synaptic dopamine (DA) release after a single oral dose of levodopa (LD) in patients with advanced Parkinson diseaseOBJECTIVE: To evaluate the relationship between clinical improvement and in vivo synaptic dopamine (DA) release after a single oral dose of levodopa (LD) in patients with advanced Parkinson disease (PD). METHODS: We studied 16 patients with advanced PD with [(11)C]raclopride (RAC) PET. Each patient had RAC PET twice: once when medication had been withdrawn and once after an LD challenge. On the day of the LD challenge scan, oral 250 mg LD/25 mg carbidopa was given before scanning. Unified Parkinson's Disease Rating Scale (UPDRS) motor scores were rated in an "off" state before LD and again at the end of PET. RESULTS: All the patients were still in "on" state at the end of their LD challenge RAC PET scans. Following LD, mean caudate and putamen RAC binding potentials (BPs) were significantly lower vs baseline, consistent with increased synaptic DA. Individual LD-induced improvements in UPDRS score correlated significantly with reductions in putaminal BP. Additionally, large putaminal RAC BP changes were associated with higher dyskinesia scores. When motor UPDRS subitems were examined, improvements in rigidity and bradykinesia, but not in tremor or axial symptoms, correlated with putamen DA release. CONCLUSION: In advanced Parkinson disease, the improvement of rigidity and bradykinesia and the presence of dyskinesias after a single dose of oral levodopa are governed by the level of dopamine generated at striatal D2 receptors. In contrast, relief of parkinsonian tremor and axial symptoms is not related to striatal synaptic dopamine levels and presumably occurs via extrastriatal mechanisms.

• Microglial activation correlates with severity in Huntington disease: a clinical and PET study.

  Authors: N Pavese, A Gerhard, Y F Tai, A K Ho, F Turkheimer, R A Barker, D J Brooks, P Piccini

  Neurology. 07/2006; 66(11):1638-43.

  BACKGROUND: Huntington disease (HD) is characterized by the progressive death of medium spiny dopamine receptor bearing striatal GABAergic neurons. In addition, microglial activation in the areas ofBACKGROUND: Huntington disease (HD) is characterized by the progressive death of medium spiny dopamine receptor bearing striatal GABAergic neurons. In addition, microglial activation in the areas of neuronal loss has recently been described in postmortem studies. Activated microglia are known to release neurotoxic cytokines, and these may contribute to the pathologic process. METHODS: To evaluate in vivo the involvement of microglia activation in HD, the authors studied patients at different stages of the disease using [(11)C](R)-PK11195 PET, a marker of microglia activation, and [(11)C]raclopride PET, a marker of dopamine D2 receptor binding and hence striatal GABAergic cell function. RESULTS: In HD patients, a significant increase in striatal [(11)C](R)-PK11195 binding was observed, which significantly correlated with disease severity as reflected by the striatal reduction in [(11)C]raclopride binding, the Unified Huntington's Disease Rating Scale score, and the patients' CAG index. Also detected were significant increases in microglia activation in cortical regions including prefrontal cortex and anterior cingulate. CONCLUSIONS: These [(11)C](R)-PK11195 PET findings show that the level of microglial activation correlates with Huntington disease (HD) severity. They lend support to the view that microglia contribute to the ongoing neuronal degeneration in HD and indicate that [(11)C](R)-PK11195 PET provides a valuable marker when monitoring the efficacy of putative neuroprotecting agents in this relentlessly progressive genetic disorder.