Parkinson Disease: Brooks DJ

Brooks DJ, Doder M. · No affiliation provided · Curr Opin Neurol. · Pubmed #11470962 No free full text.

This publication has no abstract.

Brooks DJ. · No affiliation provided · J Neurol Neurosurg Psychiatry. · Pubmed #10811688 links to  free full text

This publication has no abstract.

Brooks DJ. · Division of Neuroscience and Medical Research Council Clinical Sciences Centre, Imperial College, Hammersmith Hospital, Du Cane Road, London, United Kingdom. · Semin Neurol. · Pubmed #18843572 No free full text.

Abstract: In this article, after providing a description of the technique of brain positron emission tomography (PET), the review focuses on the application of PET and other recent advances of neuroimaging in understanding the structural, pathophysiological, and pharmacological changes associated with Parkinson's disease (PD). In early cases of PD, demonstration of the presence of nigral structural abnormalities with transcranial sonography and striatal dopaminergic dysfunction with functional imaging provides a rationale for the use of dopaminergic medications. The presence of altered striatal signal with diffusion-weighted magnetic resonance imaging (DWI) or reduced lentiform nucleus glucose metabolism with fluorodeoxyglucose PET suggests the presence of an atypical PD variant. Finally, the value of functional imaging as a biomarker for following the progression of PD and for understanding mechanisms of dementia when present is debated.

Brooks DJ, Anonymous00186. · Faculty of Medicine at Imperial College, London, UK. · Nat Clin Pract Neurol. · Pubmed #18382437 No free full text.

Abstract: Currently, the clinical diagnosis of Parkinson's disease (PD) can be problematic, particularly at the early stages of the disease when the full spectrum of symptoms and signs might not yet be manifest. In addition, the mechanisms that underlie the nonmotor complications of PD, such as dementia and depression, are poorly understood, despite the fact that these symptoms largely determine the patient's quality of life at the end stage of the disease. This article reviews the latest advances in structural and functional imaging that have provided important insights into the structural, pathophysiological and pharmacological changes associated with PD. The contribution of inflammatory processes to the pathology of PD is discussed, as are the various possible mechanisms that lead to coexistent dementia and depression.

Brooks DJ. · MRC Clinical Sciences Centre and Division of Neuroscience and Mental Health, Faculty of Medicine, Imperial College, Hammersmith Hospital, London, UK. · Parkinsonism Relat Disord. · Pubmed #18267249 No free full text.

Abstract: In this article the value of structural and functional imaging in aiding the diagnosis and management of Parkinson's disease is reviewed. The underlying pathological mechanisms leading to tremor, coexistent dementia and depression in PD are considered and the role of imaging as a biomarker for testing neuroprotective agents debated.

Lippa CF, Duda JE, Grossman M, Hurtig HI, Aarsland D, Boeve BF, Brooks DJ, Dickson DW, Dubois B, Emre M, Fahn S, Farmer JM, Galasko D, Galvin JE, Goetz CG, Growdon JH, Gwinn-Hardy KA, Hardy J, Heutink P, Iwatsubo T, Kosaka K, Lee VM, Leverenz JB, Masliah E, McKeith IG, Nussbaum RL, Olanow CW, Ravina BM, Singleton AB, Tanner CM, Trojanowski JQ, Wszolek ZK, Anonymous00243. · Department of Neurology, Drexel University College of Medicine, Philadelphia, PA 19102, USA. · Neurology. · Pubmed #17353469 No free full text.

Abstract: For more than a decade, researchers have refined criteria for the diagnosis of dementia with Lewy bodies (DLB) and at the same time have recognized that cognitive impairment and dementia occur commonly in patients with Parkinson disease (PD). This article addresses the relationship between DLB, PD, and PD with dementia (PDD). The authors agreed to endorse "Lewy body disorders" as the umbrella term for PD, PDD, and DLB, to promote the continued practical use of these three clinical terms, and to encourage efforts at drug discovery that target the mechanisms of neurodegeneration shared by these disorders of alpha-synuclein metabolism. We concluded that the differing temporal sequence of symptoms and clinical features of PDD and DLB justify distinguishing these disorders. However, a single Lewy body disorder model was deemed more useful for studying disease pathogenesis because abnormal neuronal alpha-synuclein inclusions are the defining pathologic process common to both PDD and DLB. There was consensus that improved understanding of the pathobiology of alpha-synuclein should be a major focus of efforts to develop new disease-modifying therapies for these disorders. The group agreed on four important priorities: 1) continued communication between experts who specialize in PDD or DLB; 2) initiation of prospective validation studies with autopsy confirmation of DLB and PDD; 3) development of practical biomarkers for alpha-synuclein pathologies; 4) accelerated efforts to find more effective treatments for these diseases.

Brooks DJ. · MRC Clinical Sciences Centre and Division of Neuroscience and Mental Health, Faculty of Medicine, Imperial College, Hammersmith Hospital, London, UK. · Mol Imaging Biol. · Pubmed #17340229 No free full text.

Abstract: In Parkinson's disease (PD), there is degeneration of the cholinergic, noradrenergic, and serotonergic systems in addition to dopaminergic projections. Function of these non-dopaminergic systems can be imaged with positron emission tomography (PET) and single photon emission computed tomography (SPECT) and correlated with motor and nonmotor symptomatology. In addition, neuronal loss in PD is associated with microglial activation. The role of microglia in driving the disease process remains uncertain. This review presents and discusses current findings in these areas.

Brooks DJ. · MRC Clinical Sciences Centre, Division of Neuroscience, Faculty of Medicine, Imperial College, London, UK. · J Neurol. · Pubmed #16944357 No free full text.

Abstract: 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.

Piccini P, Brooks DJ. · MRC Clinical Sciences Centre and Division of Neuroscience and Mental Health, Imperial College, Hammersmith Hospital, London, United Kingdom. · Mov Disord. · Pubmed #16874751 No free full text.

Abstract: Parkinson's disease (PD) and related disorders are subcortical degenerations targeting the nigrostriatal dopaminergic system and basal ganglia. Traditionally, MRI has been used to detect structural and positron emission tomography and single emission computed tomography functional neurochemical and metabolic changes associated with these disorders. Recently, advances in diffusion-weighted MRI, ultrasonography, and radiotracer-based imaging have yielded greater sensitivity for revealing structural change and allowed detection of changes in brain dopamine levels after levodopa and during behavioral tasks. This review focuses on these recent advances in neuroimaging technology and their use for the diagnosis and assessment of PD and other parkinsonian disorders.

Brooks DJ, Piccini P. · MRC Clinical Sciences Centre and Division of Neuroscience, Faculty of Medicine, Imperial College London, United Kingdom. · Biol Psychiatry. · Pubmed #16581032 No free full text.

Abstract: Positron emission tomography (PET) and single photon emission computed tomography (SPECT) can measure striatal dopamine (DA) terminal function in vivo as reflected by DA storage capacity and transporter binding. In Parkinson's disease (PD) posterior dorsal putamen DA terminals are initially targeted, the anterior putamen and head of caudate subsequently becoming affected. In contrast, dopaminergic function in pallidal, amygdala, and cingulate regions is upregulated in early PD and only later becomes reduced. Rigidity and bradykinesia in PD have been shown to correlate with loss of putamen dopaminergic function, whereas performance on executive and working memory tasks correlates with integrity of caudate dopaminergic terminals. 11C-RTI32 PET, a marker of noradrenergic and dopaminergic transporter binding, can be used to assess noradrenergic along with dopaminergic terminal function. Serotonergic transporter binding can be assessed with 11C-DASB PET and 123I-beta CIT SPECT, whereas HT1A binding can be measured with 11C-WAY100635 PET. With these modalities, the relationship between mood, noradrenergic and serotonergic function can be examined in PD. The functional effects of focal DA replacement on DA storage capacity and patterns of brain activation via implantation of fetal midbrain cells or glial derived neurotrophic factor (GDNF) infusion into putamen of PD patients has been examined with PET. Both approaches lead to consistently increased levels of putamen 18F-dopa uptake, and cell implantation can restore levels of frontal activation. Clinical outcome, however, has proved to be variable and off-medication dyskinesias are an unwanted side effect in transplanted cases. Dopamine release after pharmacological challenges or during behavioral tasks can be assessed indirectly by studying changes in receptor availability to PET radioligands. Stereotyped sequential movements are associated with striatal DA release, and this increases with more complex behaviors and the presence of financial incentives, which also increase frontal DA levels. Parkinson patients release less putamen DA than healthy control subjects during stereotyped finger movements. Interestingly, those PD patients who develop a dopa dependency syndrome, craving their medication, generate significantly greater levels of ventral striatal DA compared with similarly disabled patients without such a psychological dependency. In the future, functional imaging is likely to throw light on the roles of peptide transmission in regulating mood and behavior as non-peptide analogue ligands become available. Novel markers of amyloid plaque load will also help clarify the etiology of dementia in PD.

Brooks DJ. · Medical Research Council Clinical Sciences Centre and Division of Neuroscience, Faculty of Medicine, Imperial College, Hammersmith Hospital, London W12 ONN, United Kingdom. · NeuroRx. · Pubmed #15717049 links to  free full text

Abstract: In this article, the role of functional imaging for providing objective evidence that grafts of fetal tissue can survive and form connections in Parkinson's and Huntington's disease patients is reviewed. The dissociation between dopamine storage capacity, clinical improvement, and normalization of brain metabolism in PD is discussed, and possible mechanisms underlying the phenomenon of dyskinesias off medication are presented. It is concluded the positron emission tomography and single photon emission computed tomography can provide valuable ancillary information alongside clinical observations but are not currently appropriate modalities for use as surrogate endpoints.

Brooks DJ. · Medical Research Council Clinical Sciences Center and Division of Neuroscience, Faculty of Medicine, Imperial College, Hammersmith Hospital, London W12 0NN, United Kingdom. · NeuroRx. · Pubmed #15717025 links to  free full text

Abstract: In this review, the potential role of positron emission tomography and single photon emission computed tomography as biological markers for diagnosing and following the progression of Parkinson's disease (PD) is discussed. Their value for assessing the efficacy of putative neuroprotective agents in PD and for revealing the pharmacological changes underlying the symptomatology and complications of this disorder is also considered. It is concluded that in the future functional imaging will provide a valuable adjunct to clinical assessment when judging the efficacy of putative neuroprotective approaches to PD.

Ravina B, Eidelberg D, Ahlskog JE, Albin RL, Brooks DJ, Carbon M, Dhawan V, Feigin A, Fahn S, Guttman M, Gwinn-Hardy K, McFarland H, Innis R, Katz RG, Kieburtz K, Kish SJ, Lange N, Langston JW, Marek K, Morin L, Moy C, Murphy D, Oertel WH, Oliver G, Palesch Y, Powers W, Seibyl J, Sethi KD, Shults CW, Sheehy P, Stoessl AJ, Holloway R. · National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA. · Neurology. · Pubmed #15668415 No free full text.

Abstract: Radiotracer imaging (RTI) of the nigrostriatal dopaminergic system is a widely used but controversial biomarker in Parkinson disease (PD). Here the authors review the concepts of biomarker development and the evidence to support the use of four radiotracers as biomarkers in PD: [18F]fluorodopa PET, (+)-[11C]dihydrotetrabenazine PET, [123I]beta-CIT SPECT, and [18F]fluorodeoxyglucose PET. Biomarkers used to study disease biology and facilitate drug discovery and early human trials rely on evidence that they are measuring relevant biologic processes. The four tracers fulfill this criterion, although they do not measure the number or density of dopaminergic neurons. Biomarkers used as diagnostic tests, prognostic tools, or surrogate endpoints must not only have biologic relevance but also a strong linkage to the clinical outcome of interest. No radiotracers fulfill these criteria, and current evidence does not support the use of imaging as a diagnostic tool in clinical practice or as a surrogate endpoint in clinical trials. Mechanistic information added by RTI to clinical trials may be difficult to interpret because of uncertainty about the interaction between the interventions and the tracer.

Brooks DJ. · MRC Clinical Sciences Centre, Faculty of Medicine, Imperial College London, Hammersmith Hospital, United Kingdom. · Neurology. · Pubmed #14718679 No free full text.

Abstract: Combining levodopa with the catechol-O-methyltransferase (COMT) inhibitor entacapone has been shown to be an effective strategy in the management of Parkinson's disease (PD) patients experiencing motor fluctuations. Safety and tolerability information has come from postmarketing surveillance studies as well as several randomized, placebo-controlled trials with long-term open-label extension phases specifically investigating the safety and tolerability of levodopa plus entacapone. Results show the most common dopaminergic side effects to be dyskinesia and nausea, which result from the increased bioavailability of levodopa and can be readily managed. Non-dopaminergic side effects include diarrhea and harmless urine discoloration. There is no convincing evidence of hepatic injury with entacapone use, and therefore monitoring of liver enzymes is unnecessary. With over 300,000 patient-years of exposure, levodopa combined with entacapone can be considered safe and well tolerated.

Brooks DJ, Frey KA, Marek KL, Oakes D, Paty D, Prentice R, Shults CW, Stoessl AJ. · MRC Faculty of Medicine, Imperial College, London, UK. · Exp Neurol. · Pubmed #14597329 No free full text.

Abstract: A major goal of research in Parkinson's disease (PD) has been the development of treatments to slow the progressive degeneration of the nigrostriatal dopaminergic system and to reduce the functional decline of patients. Because of the uncertainty in the ability of the clinical evaluation to reflect the status of the nigrostriatal dopaminergic system once dopaminergic therapy has commenced, investigators in PD have sought to develop alternative measures of disease. One approach, which has been extensively explored, is neuroimaging with radiotracers that interact with processes central to dopaminergic neurotransmission in the nigrostriatal dopaminergic axons-conversion of levodopa to dopamine through aromatic amino acid decarboxylase (AADC), [(18)F]fluorodopa PET, storage of dopamine in synaptic vesicles via the vesicular monoamine transporter 2 (VMAT2), (+)-[(11)C]dihydrotetrabenazine PET, and reuptake of dopamine into axons via the dopamine transporter (DAT), [(123)I]beta-CIT SPECT, and a number of other PET and SPECT ligands. During the 54(th) Annual Meeting of the American Academy of Neurology, a group of investigators active in the fields of biomakers, neuroimaging, and neuroprotection met to review the three techniques mentioned above. Prior to the meeting, the participants developed consensus on a set of 10 criteria for a neuroimaging technique to be considered adequate as a biomarker for progression of PD and levels at which the available data for each technique indicate that the criterion was met. The criteria and each of the three imaging techniques mentioned above were reviewed, and the results of that meeting are presented.

Brooks DJ. · MRC Clinical Sciences Centre, Faculty of Medicine, Imperial College, London, UK. · Ann N Y Acad Sci. · Pubmed #12846971 No free full text.

Abstract: Positron emission tomography (PET) can detect the presence of striatal, pallidal, midbrain, and cortical dopamine terminal dysfunction in vivo in Parkinson's disease (PD). In addition, dopamine release during motor tasks can be assessed as reflected by changes in receptor availability to PET ligands. Furthermore, the functional effects of focal dopamine replacement via implantation of fetal cells or glia-derived neurotrophic factor (GDNF) infusion into putamen can be monitored. In this review, the insight that PET has given us concerning the role of dopamine in motor control is presented, and the functional substrates underlying PD symptomatologies are discussed.

Brooks DJ. · MRC Clinical Sciences Centre and Division of Neuroscience, Faculty of Medicine, Imperial College, Hammersmith Hospital, London, United Kingdom. · Ann Neurol. · Pubmed #12666103 No free full text.

Abstract: In this review, the potential role of positron emission tomography and single-photon emission computed tomography as biological markers for following the progression of Parkinson's disease (PD) is discussed, and their value for assessing the efficacy of putative neuroprotective agents in PD is considered. It is concluded that functional imaging provides a valuable adjunct to clinical assessment when judging the efficacy of neuroprotective approaches to PD.

Brooks DJ. · Department of Neurology, Imperial College School of Medicine, Hammersmith Hospital, London W12 0NN, U.K. · Adv Neurol. · Pubmed #11553981 No free full text.

This publication has no abstract.

Bhatia K, Brooks DJ, Burn DJ, Clarke CE, Grosset DG, MacMahon DG, Playfer J, Schapira AH, Stewart D, Williams AC, Anonymous00286. · University Department of Clinical Neurology, Institute of Neurology, London. · Hosp Med. · Pubmed #11530583 No free full text.

Abstract: New data on diagnosis, drug therapy, surgery and psychosocial concerns have emerged since the publication of the 1998 Guidelines for the Management of Parkinson's Disease. This article reviews new data and addresses issues left unanswered in the previous guidelines.

Brooks DJ. · MRC Clinical Sciences Centre, Imperial College School of Medicine, Hammersmith Hospital, London, UK. · J Neural Transm Suppl. · Pubmed #11205135 No free full text.

Abstract: In this article the role of functional imaging (PET and SPECT) as a surrogate marker for following the progression of Parkinson's disease (PD) is discussed. The potential value of PET and SPECT for assessing the efficacy of putative neuroprotective agents in PD is considered and a review of 18F-dopa PET findings in transplantation trials involving implantation of human and procine fetal mesencephalic tissue is presented. It is concluded that functional imaging provides a valuable adjunct to clinical assessment when judging the efficacy of neuroprotective and restorative approaches to PD.

Brooks DJ, Samuel M. · MRC Cyclotron Unit, Imperial College School of Medicine, Hammersmith Hospital, London, United Kingdom. · Neurology. · Pubmed #11188976 No free full text.

Abstract: Positron emission tomography allows a quantitative assessment of the impact of functional neurosurgery in Parkinson's disease (PD) by measuring regional cerebral flow and glucose and oxygen consumption as indicators of metabolic activity of specific brain regions. PET can also be used to study the dopaminergic nigrostriatal system, and therefore serves as a surrogate marker of the evolution of striatal grafts for PD. Pallidotomy has been associated with increased activation of premotor areas (supplementary motor area and dorsolateral prefrontal cortex) and reduced hyperactivity of the lentiform nucleus (augmented preoperatively). Pallidal (GPi) and subthalamic (STN) stimulation also increase activation of premotor areas but decrease activation of primary motor area. Suppression of unilateral tremor with thalamic stimulation is associated with a reduction in cerebellar blood flow. These main findings are in keeping with the general notion that increased activity in the STN GPi projection is directly implicated in the pathophysiology of PD. Surgical blockage of these output nuclei leads to partial restoration of cortical physiology.

Brooks DJ, Piccini P. · MRC Cyclotron Unit, Hammersmith Hospital, London W12 0NN, UK. · Prog Brain Res. · Pubmed #11142033 No free full text.

This publication has no abstract.

Brooks DJ. · MRC Clinical Sciences Centre, Imperial College School of Medicine, Hammersmith Hospital, London, UK. · Trends Neurosci. · Pubmed #11052227 No free full text.

Abstract: Parkinson's disease (PD) patients with motor complications show a greater reduction in putamen [18F]dopa uptake on positron emission tomography (PET) compared with sustained responders to L-dopa, although individual ranges overlap considerably. This implies that, although loss of putamen dopamine storage predisposes motor complications in PD, it cannot be the only factor determining timing of onset. Additional PET studies suggest that loss of striatal dopamine storage capacity along with pulsatile exposure to exogenous L-dopa results in pathologically raised synaptic dopamine levels and deranged basal ganglia opioid transmission.This, rather than altered dopamine receptor binding, then causes inappropriate overactivity of basal ganglia-frontal projections, resulting in breakthrough involuntary movements.

Brooks DJ. · MRC Cyclotron Unit, Imperial College School of Medicine, Hammersmith Hospital, London, UK. · J Neurol. · Pubmed #10991656 No free full text.

Abstract: This paper reviews the relative abilities of magnetic resonance imaging (MRI), positron emission tomography (PET), single photon emission tomography (SPECT), and proton magnetic resonance spectroscopy (MRS) to detect Parkinson's disease and monitor its progression. Currently, the main role of MRI lies in its ability to discriminate atypical syndromes from Parkinson's disease; however, new volumetric approaches may soon allow progression of nigral degeneration to be followed. Proton MRS can also detect reduced levels of putamen N-acetyl aspartate (NAA) in many patients with atypical parkinsonian syndromes. PET and SPECT are both sensitive means of detecting the presence of impaired dopamine terminal function in the striatum and following its progression. PET currently has the greater spatial resolution and provides the added advantages that it also allows extra-striatal dopaminergic function to be monitored.

Brooks DJ. · MRC Cyclotron Unit, Imperial College School of Medicine, Hammersmith Hospital, London, UK. · J Anat. · Pubmed #10923986 links to  free full text

Abstract: In this review, the value of functional imaging for providing insight into the role of the basal ganglia in motor control is reviewed. Brain activation findings in normal subjects and Parkinson's disease patients are examined and evidence supporting the existence for functionally independent distributed basal ganglia-frontal loops is presented. It is argued that the basal ganglia probably act to focus and filter cortical output, optimising the running of motor programs.