0
We're unable to sign you in at this time. Please try again in a few minutes.
Retry
We were able to sign you in, but your subscription(s) could not be found. Please try again in a few minutes.
Retry
There may be a problem with your account. Please contact the AMA Service Center to resolve this issue.
Contact the AMA Service Center:
Telephone: 1 (800) 262-2350 or 1 (312) 670-7827  *   Email: subscriptions@jamanetwork.com
Error Message ......
Neurological Review |

Overview of the Extranigral Aspects of Parkinson Disease FREE

Shen-Yang Lim, MBBS, FRACP; Susan H. Fox, PhD, MRCP; Anthony E. Lang, MD, FRCPC
[+] Author Affiliations

Author Affiliations:Movement Disorders Centre, Toronto Western Hospital, Toronto, Ontario, Canada.


Section Editor: David E. Pleasure, MD

More Author Information
Arch Neurol. 2009;66(2):167-172. doi:10.1001/archneurol.2008.561.
Text Size: A A A
Published online

In recent years, there has been increasing recognition of the features of Parkinson disease that are not related to nigrostriatal dopamine deficiency. This review addresses selected clinical, anatomic, pathologic, and biochemical correlates of the early premotor symptoms of Parkinson disease, later nonmotor fluctuations, and advanced dopa-unresponsive motor and nonmotor features. The recognition of early features that predate classic motor symptoms will be important as effective neuroprotective therapy becomes available. Later-stage features often contribute markedly to disability and impaired quality of life and, therefore, represent an important future therapeutic challenge.

Figures in this Article

Loss of substantia nigra pars compacta (SNc) dopaminergic neurons is considered to be the most important neuropathologic hallmark of Parkinson disease (PD). Focus on the nigrostriatal dopaminergic system is justified by the prominent motor manifestations for which patients seek treatment and the remarkable success of dopamine replacement therapy. However, it has become increasingly apparent that the neuropathologic changes of PD extend well beyond the nigrostriatal system (Figure). Even components of the early core motor symptoms may not be exclusively related to nigrostriatal dopamine deficiency. This is particularly the case for tremor for which animal models and clinical, pharmacologic, positron emission tomography, and postmortem studies support an important role for extranigral mechanisms (Table 1).1Most of the disability brought on by advancing PD relates to the emergence of symptoms that respond poorly, if at all, to levodopa or modern surgical therapies; these disabilities include “on”-medication axial motor features such as gait freezing, postural instability with falls, dysarthria and dysphagia, and a broad spectrum of nonmotor symptoms. Nonmotor symptoms comprise a variety of neuropsychiatric, autonomic, sensory, and sleep disorders. Although some of these symptoms, such as dementia and psychosis, typically appear late in the course of the disease, other nonmotor symptoms may occur early in the disease, even before the onset of motor problems, and many continue to be common across all stages of PD. Although the anatomic, pathologic, and biochemical substrates for much of the PD symptom complex are yet to be fully characterized, significant progress has been made. Pathologic changes occur in widespread regions of the central and peripheral nervous systems, and it is recognized that many different neurotransmitter systems (eg, noradrenergic, serotonergic, and cholinergic) in addition to dopamine are deranged as part of the multisystem neurodegeneration that constitutes PD. Increasing evidence suggests that in most cases the first neurons affected in PD are nondopaminergic, and the SNc may become involved only after the disease is well established in other regions of the nervous system.2Indeed, α-synuclein–containing Lewy bodies (LBs), the histologic hallmark of PD, were first described almost a century ago in the nondopaminergic neurons of the dorsal motor nucleus of the vagal nerve, nucleus basalis of Meynert, and hypothalamus. On the other hand, abnormalities in extranigral dopaminergic systems (mesolimbic, mesocortical, and thalamic) also likely contribute to the PD symptom complex.

Place holder to copy figure label and caption
Figure.

Putative anatomic substrates for the nonmotor features of Parkinson disease. ANS indicates autonomic nervous system; DMNV, dorsal motor nucleus of the vagal nerve; LC, locus ceruleus; PPN, pedunculopontine nucleus; RBD, rapid eye movement behavior disorder; and RpN, raphe nuclei.

Graphic Jump Location

Table Graphic Jump LocationTable 1. Possible Clinicopathologic Correlates of Parkinsonian Tremor and Other (Later Stage) Extranigral Features and Treatments

A number of nonmotor features can precede the motor symptoms of PD. These symptoms probably arise from extranigral structures. Two types of studies provide important insights into this issue: (1) the prospective evaluation of individuals who eventually developed overt PD and (2) the evaluation of individuals whose brains show evidence of incidental Lewy body disease (ILBD). The term ILBDis used when LBs and Lewy neurites (α-synuclein inclusions) are found in the central nervous system of individuals without clinically documented parkinsonism or dementia. The distribution of the inclusions, neurochemical changes, and neuronal counts support the hypothesis that ILBD represents preclinical PD (or dementia with LBs), with lack of motor symptoms due to the subthreshold severity of the disease.3

Table 2lists those features that have been convincingly shown to occur well before the onset of parkinsonism, in some cases preceding it by decades. However, these features are not universally present, and most are so common and nonspecific that they alone could not predict which patients might be in the earliest stages of the disease (for trials of neuroprotective therapies). Olfactory deficits and cardiac sympathetic denervation are present in a high proportion of patients who present with the earliest motor signs, which suggests that such features probably precede the motor signs and may be more useful in characterizing early disease status. Other features documented in a smaller proportion of patients early in the course of the disease include pain, orthostatic hypotension, urinary urgency, and executive dysfunction found on neuropsychological testing.

Table Graphic Jump LocationTable 2. Early Premotor Features of PD

The widely cited work of Braak and colleagues2emphasizes the importance of early extranigral involvement in PD. Applying modern immunohistochemical techniques to a large autopsy population, these authors proposed a pattern of PD progression.2Their work suggests that PD generally begins in the anterior olfactory nucleus and medulla (including the dorsal motor nucleus of the vagal nerve) and ascends through the brain in a predictable sequence that eventually involves the entire neocortex. According to this scheme, SNc degeneration does not occur until an intermediate stage (stage 3 of 6 stages) is reached in the temporal sequence of PD, with motor symptoms emerging in stage 3 or 4.

Although the Braak staging scheme with its implications to the premotor features of PD has been largely confirmed by other investigators,3several criticisms of this work have been raised. There remains uncertainty regarding the impact of α-synuclein disease on neuronal function and survival. Exclusion of cases of dementia with LBs and the fact that ILBD cases were preselected for the presence of α-synuclein deposition in the dorsal motor nucleus of the vagal nerve raise the possibility of selection bias. Since Braak's original report, examples have been reported in which α-synuclein inclusions have been detected at higher levels in the neuraxis but absent in 1 or more vulnerable caudal nuclei. A final criticism is that the original studies and staging scheme did not include the spinal cord and peripheral autonomic nervous system.

The early involvement of the anterior olfactory nucleus is a likely cause of hyposmia in PD (and ILBD). In Braak stages 1 and 2, in addition to the anterior olfactory nucleus, lower brainstem structures, including the dorsal motor nucleus of the vagal nerve, locus ceruleus, and raphe nuclei, are involved. The locus ceruleus and raphe nuclei project widespread connections (noradrenergic and serotonergic, respectively) to many brain regions, as well as to the spinal cord. Although the specific cause of rapid eye movement (REM) behavior disorder in PD is unknown, postmortem examination of patients with idiopathic REM behavior disorder has documented severe LB involvement and/or neuronal loss in the locus ceruleus and substantia nigra as the most significant histopathologic findings.8The role of γ-aminobutyric acid (GABA) in mediating REM sleep has been recently suggested, with a complex interaction between brainstem noradrenergic and serotonergic neurons, which switch from a REM-on to a REM-off state, depending on the inhibitory effects of GABA. The current treatment of choice for REM behavior disorder is the benzodiazepine clonazepam, which influences GABAergic function. Involvement of the locus ceruleus (1 of several subcortical noradrenergic regions that have wakefulness-promoting actions) is a postulated cause of daytime hypersomnolence occurring early in PD. The association between hypersomnolence and longer PD duration and greater motor severity suggests that progressive involvement of additional structures, such as hypocretin-producing neurons in the hypothalamus (with the hypothalamus affected as early as Braak stage 3), may also be important. Noradrenergic and serotonergic dysfunction may underlie symptoms of depression and anxiety. This theory is supported by older postmortem and cerebrospinal fluid 5-hydroxyindoleacetic acid studies; more recent functional imaging studies using positron emission tomography, single-photon emission computed tomography, and transcranial ultrasonography; and the response of these symptoms to selective serotonin reuptake inhibitors and serotonin-norepinephrine reuptake inhibitors.17Positron emission tomography studies17also support a role of cortical and subcortical limbic dopamine projections in depression. Pathologic changes in the locus ceruleus, raphe nuclei, mesolimbic system, and hypothalamus (as well as in the spinal cord dorsal horn and thalamus) have been postulated to underlie PD-related pain.

Although the Braak staging system does not include a description of LB disease in the spinal cord or peripheral nervous system, neuropathologic studies of PD and ILBD have demonstrated early involvement of autonomic neurons in the thoracic and sacral spinal cord, heart, and gastrointestinal and genitourinary tracts.3Cardiac uptake on metaiodobenzylguanidine 123–labeled scintigraphy, a specific marker for noradrenergic transporters, is reduced in nearly all patients with PD, even at the earliest stage of the disease and in idiopathic REM behavior disorder, and cardiac sympathetic denervation is also found in ILBD.3In addition, LBs have been found in the lower esophagus and small intestine of nonparkinsonian patients without ILBD in the central nervous system, suggesting that in some cases LB disease may begin outside the brain; this result has also rarely been reported for LBs in the adrenal gland.18It is intriguing to consider the possibility that PD may actually begin in the peripheral autonomic nervous system and only later involve the central nervous system.

Most patients experiencing motor fluctuations after long-term oral levodopa therapy also identify nonmotor fluctuations. Symptoms such as anxiety, sadness, slowness of thinking, fatigue, apathy, drenching sweats, urinary urgency, and pain (dystonic or nondystonic), are usually associated with the “off”-medication state, whereas hypomanic symptoms may occur during the “on”-medication state. The response of some but not all of these symptoms to subthalamic nucleus deep brain stimulation suggests varied pathogeneses that involve the basal ganglia motor circuit influenced by this treatment and other areas affected by long-term pulsatile dopaminergic therapy. Antiparkinsonian treatment may also be complicated by the development of impulse control disorders, such as pathologic gambling and shopping, binge eating, and hypersexuality, increasingly recognized problems in treated PD patients. Less commonly, addiction to dopaminergic agents (dopamine dysregulation syndrome [DDS]) is seen.

The cause of dopamine-induced fluctuations in many of the nonmotor symptoms experienced by PD patients remains unknown. We briefly discuss the possible correlates of motivation and mood changes in PD. In Braak stage 3, the medial SNc and ventral tegmental area become affected, resulting in loss of dopaminergic fibers to the caudate nucleus, nucleus accumbens, amygdala, anterior cingulate cortex, and other limbic and frontal cortical areas where dopamine is essential for mediating mood, working memory, reward-related learning, and motivation. Thus, mesolimbic and mesocortical dopamine deficiency may underlie some of the nonmotor symptoms that occur in the “off”-medication state. On the other hand, it has been postulated that the relative preservation of ventral striatal dopamine, compared with the dorsal striatum, may result in dopaminergic medication–induced overdosing of the ventral striatum in some patients that may increase impulsivity19and underlie abnormal reward-driven behaviors, such as impulse control disorders and DDS. For example, Evans et al20demonstrated a link between compulsive dopaminergic drug use (as part of DDS) and abnormal (“sensitized”) mesolimbic dopaminergic transmission. Abnormal dopaminergic modulation of the limbic system may also be responsible for levodopa-related fluctuations in mood21and pain, symptoms that are often exaggerated in DDS.

Dementia, Visual Hallucinations, and Dopa-Unresponsive Motor Disability

Although the effect of levodopa on bradykinesia, rigidity, and tremor remains relatively stable during the course of the disease, the response for axial problems, such as postural instability, gait disorder, and speech impairment, declines.22In these patients, the best motor response to a suprathreshold dose of levodopa becomes incomplete and insufficient. A related observation is that in most patients with an initial tremor-dominant phenotype, the clinical picture shifts during the disease to a postural instability and gait dysfunction phenotype. This transition is apparently unidirectional and irreversible and is associated with accelerated cognitive decline and a highly increased risk for subsequent dementia,23consistent with other studies demonstrating a clear relationship between axial symptoms and cognitive decline in PD. As PD progresses, many patients develop frank dementia. For example, the community-based Sydney multicenter study, which is the longest prospective study of PD, reported a disturbing 83% frequency of dementia 20 years after PD diagnosis (mean age, 74 years); falls, gait freezing, moderate dysarthria, choking, and hallucinations were experienced by 87%, 81%, 81%, 48%, and 74% of patients, respectively. Once dementia was diagnosed, the median survival was 4.5 years. Similarly, Williams and Lees24reported that patients have generally passed the halfway mark in the course of their disease when visual hallucinations develop, with a mean survival of 4.4 years after the onset of this symptom.

CLINICOPATHOLOGIC CORRELATES OF ADVANCED PD

In the latter half of the Braak staging scheme, LBs spread into limbic areas (stage 4), cortical association areas (stage 5), and finally primary cortical areas (stage 6). Limbic and cortical LB disease have been shown to be the main morphologic substrates of PD dementia (PDD).25However, Braak et al25showed that even in stage 3 (ie, in the virtual absence of cortical LB involvement), a third of patients already had impaired cognition, mostly of moderate severity. Conversely, Colosimo et al26described a series of PD patients with considerable limbic and/or neocortical LB involvement but without important cognitive impairment. In addition, later-stage cortical involvement generally occurs against a backdrop of the already advanced destruction of vulnerable subcortical nuclei; in autopsy studies, PDD has been associated with neuronal loss in the locus ceruleus, medial SNc, ventral tegmental area, and nucleus basalis of Meynert. Although some authors have emphasized impaired mesolimbic and mesocortical dopaminergic function in PDD, a severe cortical cholinergic deficit, independent of coexistent Alzheimer disease changes, is the most consistent neurochemical finding associated with PDD,27and cholinesterase inhibitors are frequently more effective in PDD than in Alzheimer disease. The response of apathy to these agents supports a role for cholinergic systems in this feature of PD as well.28Glycinergic and especially glutamatergic factors may also play a role in PDD, although the evidence for this theory is limited. Additional Alzheimer pathologic burden in PDD is generally low but probably exacerbates the overall disease process, as does aging.29

The pathologic basis of visual hallucinations in PD may involve the inferotemporal cortex and substantia nigra pars reticulata. The inferotemporal lobe is involved in visual processing of complex features related to people and objects, as is typical in the well-formed hallucinations of PD. Lewy bodies are increased in the ventral temporal lobe in PD patients with well-formed visual hallucinations compared with those without, and cerebral blood flow is reduced in the temporal and upper temporal-occipital cortex compared with PD patients who do not halluciate.30The substantia nigra pars reticulata has been suggested as a potential site of visual hallucinations because lesions in the medial substantia nigra pars reticulata can cause vivid, well-formed hallucinations (peduncular hallucinosis) similar to those of PD. Disturbances in the sleep-wake cycle are also often found in those who hallucinate and may account for the diurnal fluctuations in these symptoms. Such patients may have more daytime somnolence and vivid dreams or nightmares, although the exact nature of this relationship is not entirely clear.31Indeed, in some patients hallucinations may relate to intrusions of REM sleep into wakefulness comparable to hypnagogic hallucinations in narcolepsy. Thus, disease in brainstem (and hypothalamic) structures controlling sleep may also cause fluctuating hallucinations in PD. Postmortem studies32show a relative preservation of serotonin 2 receptors in the temporal cortex of PD patients with hallucinations compared with PD patients who do not hallucinate. To date, the atypical neuroleptics quetiapine fumarate and clozapine, which are also serotonin 2A and 2C receptor antagonists, are the most effective treatments for hallucinations in PD. A cholinergic component is supported by the response of hallucinations in patients with dementia to cholinesterase inhibitors. The relationship between hallucinations and REM intrusions might also support a role for treating excessive daytime somnolence in these patients.

It is unlikely that the changing motor response to antiparkinsonian drugs (with the development of dopa-resistant features) is solely due to a progressive degeneration of the presynaptic nigrostriatal dopaminergic system. Involvement of extranigral structures is likely to be important. Loss of striatal neurons has been demonstrated in PD, with 1 study33reporting the presence of LBs in striatal medium-sized neurons beginning in Braak stage 3; the severity of these striatal changes correlated with the Braak stage. Changes in postsynaptic striatal and pallidal neurons, with a reduction of dopamine D3receptors, have been associated with the loss of response to dopaminergic drugs.34The pedunculopontine nucleus, which is affected in Braak stage 3, is highly interconnected with the basal ganglia and is an important relay nucleus between the basal ganglia and the spinal cord. It plays a role in postural stability and gait (as well as in regulation of the sleep-wake cycle) and is a new surgical target currently being studied in the management of axial signs that fail to respond to levodopa and subthalamic nucleus deep brain stimulation. In later Braak stages, LBs may involve premotor and rarely even primary motor cortex involvement of premotor cortical regions, such as the supplementary motor area or presupplementary motor area, may lead to dopa-unresponsive parkinsonism. Halliday et al35demonstrated an 88% loss of presupplementary motor area corticocortical projection neurons in PD patients with severe “on”-medication motor disability.

Parkinson disease is more than a disease of the nigrostriatal dopaminergic system. The neurodegenerative process affects multiple central and peripheral systems. Currently, optimal symptomatic therapy for PD often consists of a cocktail of agents with diverse pharmacologic actions. This contrasts with usual practice in conditions such as epilepsy, for which monotherapy is the goal. Although dopaminergic therapy remains the mainstay, a wide variety of nondopaminergic agents are also used as highlighted throughout this review. On the other hand, many of these symptoms respond poorly or incompletely to available therapies, further emphasizing the urgency for greater research attention to these problems. The increasing recognition of extranigral aspects of PD will ultimately lead to earlier recognition of the onset of the disease and thus improve effectiveness and use of future neuroprotective therapies. In addition, more effective treatments for many of the disabling nonmotor symptoms and late-stage dopa-resistant motor symptoms will be possible with advances in our understanding of the pathogenesis of these features.

Correspondence:Anthony E. Lang, MD, FRCPC, Movement Disorders Centre, Toronto Western Hospital, 399 Bathurst St, Toronto, Ontario M5T 2S8, Canada (lang@uhnres.utoronto.ca).

Accepted for Publication:June 17, 2008.

Author Contributions:Study concept and design: Lim, Fox, and Lang. Acquisition of data: Lim, Fox, and Lang. Analysis and interpretation of data: Lim, Fox, and Lang. Drafting of the manuscript: Lim. Critical revision of the manuscript for important intellectual content: Lim, Fox, and Lang. Obtained funding: Lang.

Financial Disclosure:None reported.

Additional Contributions:Gail Rudakewich, MS (http://synapse-visuals.com/gail.htm), provided artwork for the Figure.

Doder  MRabiner  EATurjanski  NLees  AJBrooks  DJ Tremor in Parkinson's disease and serotonergic dysfunction: an 11C-WeregAY 100635 PET study. Neurology 2003;60 (4) 601- 605
PubMed
Braak  HDel Tredici  KRüb  Ude Vos  RAIJansen Steur  ENHBraak  E Staging of brain pathology related to sporadic Parkinson's disease. Neurobiol Aging 2003;24 (2) 197- 211
PubMed
Dickson  DWFujishiro  HDelleDonne  A  et al.  Evidence that incidental Lewy body disease is pre-symptomatic Parkinson's disease. Acta Neuropathol 2008;116 (1) 125- 128
Ross  GWPetrovitch  HAbbott  RD  et al.  Association of olfactory dysfunction with risk for future Parkinson's disease. Ann Neurol 2008;63 (2) 167- 173
Ross  GWAbbott  RDPetrovitch  H  et al.  Association of olfactory dysfunction with incidental Lewy bodies. Mov Disord 2006;21 (12) 2062- 2067
PubMed
Schenck  CHBundlie  SRMahowald  MW Delayed emergence of a parkinsonian disorder in 38% of 29 older men initially diagnosed with idiopathic rapid eye movement sleep behavior disorder. Neurology 1996;46 (2) 388- 393
PubMed
Stiasny-Kolster  KDoerr  YMöller  JC  et al.  Combination of ‘idiopathic’ REM sleep behaviour disorder and olfactory dysfunction as possible indicator for α-synucleinopathy demonstrated by dopamine transporter FP-CIT-SPECT. Brain 2005;128 (pt 1) 126- 137
PubMed10.1093/brain/awj322
Boeve  BFDickson  DWOlson  EJ  et al.  Insights into REM sleep behavior disorder pathophysiology in brainstem-predominant Lewy body disease. Sleep Med 2007;8 (1) 60- 64
PubMed
Uchiyama  MIsse  KTanaka  K  et al.  Incidental Lewy body disease in a patient with REM sleep behavior disorder. Neurology 1995;45 (4) 709- 712
PubMed
Postuma  RBLang  AEMassicotte-Marquez  JMontplaisir  J Potential early markers of Parkinson disease in idiopathic REM sleep behavior disorder. Neurology 2006;66 (6) 845- 851
PubMed
Abbott  RDRoss  GWWhite  LR  et al.  Excessive daytime sleepiness and subsequent development of Parkinson disease. Neurology 2005;65 (9) 1442- 1446
PubMed
Schuurman  AGvan den Akker  MEnsinck  KTJL  et al.  Increased risk of Parkinson's disease after depression: a retrospective cohort study. Neurology 2002;58 (10) 1501- 1504
PubMed
Shiba  MBower  JHMaraganore  DM  et al.  Anxiety disorders and depressive disorders preceding Parkinson's disease: a case-control study. Mov Disord 2000;15 (4) 669- 677
PubMed
Abbott  RDPetrovitch  HWhite  LR  et al.  Frequency of bowel movements and the future risk of Parkinson's disease. Neurology 2001;57 (3) 456- 462
PubMed
Abbott  RDRoss  GWPetrovitch  H  et al.  Bowel movement frequency in late-life and incidental Lewy bodies. Mov Disord 2007;22 (11) 1581- 1586
PubMed
Gao  XChen  HSchwarzschild  MA  et al.  Erectile function and risk of Parkinson's disease. Am J Epidemiol 2007;166 (12) 1446- 1450
PubMed
Remy  PDoder  MLees  ATurjanski  NBrooks  D Depression in Parkinson's disease: loss of dopamine and noradrenaline innervation in the limbic system [published online February 16, 2005]. Brain 2005;128 (6) 1314- 1322
PubMed10.1093/brain/awh445
Fumimura  YIkemura  MSaito  Y  et al.  Analysis of the adrenal gland is useful for evaluating pathology of the peripheral autonomic nervous system in Lewy body disease. Neuropathol Exp Neurol 2007;66 (5) 354- 362
Cools  R Dopaminergic modulation of cognitive function—implications for L-dopa treatment in Parkinson's disease. Neurosci Biobehav Rev 2006;30 (1) 1- 23
PubMed
Evans  AHPavese  NLawrence  AD  et al.  Compulsive drug use linked to sensitized ventral striatal dopamine transmission. Ann Neurol 2006;59 (5) 852- 858
PubMed
Black  KJHershey  THartlein  JMCarl  JLPerlmutter  JS Levodopa challenge neuroimaging of levodopa-related mood fluctuations in Parkinson's disease. Neuropsychopharmacology 2005;30590- 601
Clissold  BGMcColl  CDReardon  KRShiff  MKempster  PA Longitudinal study of the motor response to levodopa in Parkinson's disease. Mov Disord 2006;21 (12) 2116- 2121
PubMed
Alves  GLarsen  JPEmre  MWentzel-Larsen  TAarsland  D Changes in motor subtype and risk for incident dementia in Parkinson's disease. Mov Disord 2006;21 (8) 1123- 1130
PubMed
Williams  DRLees  AJ Visual hallucinations in the diagnosis of idiopathic Parkinson's disease: a retrospective autopsy study. Lancet Neurol 2005;4 (10) 605- 610
PubMed
Braak  HRüb  UJansen Steur  ENHDel Tredici  Kde Vos  RA Cognitive status correlates with neuropathologic stage in Parkinson disease. Neurology 2005;64 (8) 1404- 1410
PubMed
Colosimo  CHughes  AJKilford  LLees  AJ Lewy body cortical involvement may not always predict dementia in Parkinson's disease. J Neurol Neurosurg Psychiatry 2003;74 (7) 852- 856
PubMed
Bohnen  NIKaufer  DIIvanco  LS  et al.  Cortical cholinergic function is more severely affected in parkinsonian dementia than in Alzheimer disease: an in vivo positron emission tomographic study. Arch Neurol 2003;60 (12) 1745- 1748
PubMed
Poewe  W Treatment of dementia with Lewy bodies and Parkinson's disease dementia. Mov Disord 2005;20 ((suppl 12)) S77- S82
PubMed
Levy  G The relationship of Parkinson disease with aging. Arch Neurol 2007;64 (9) 1242- 1246
PubMed
Harding  AJBroe  GAHalliday  GM Visual hallucinations in Lewy body disease relate to Lewy bodies in the temporal lobe. Brain 2002;125 (pt 2) 391- 403
PubMed10.1093/brain/awf033
Goetz  CGWuu  JCurgian  LMLeurgans  S Hallucinations and sleep disorders in PD: six-year prospective longitudinal study. Neurology 2005;64 (1) 81- 86
PubMed
Cheng  AVTFerrier  INMorris  CM  et al.  Cortical serotonin-S2 receptor binding in Lewy body dementia, Alzheimer's and Parkinson's diseases. J Neurol Sci 1991;106 (1) 50- 55
PubMed
Mori  FTanji  KZhang  HKakita  ATakahashi  HWakabayashi  K α-Synuclein pathology in the neostriatum in Parkinson's disease. Acta Neuropathol 2008;115 (4) 453- 459
Joyce  JNRyoo  HLBeach  TB  et al.  Loss of response to levodopa in Parkinson's disease and co-occurrence with dementia: role of D3 and not D2 receptors. Brain Res 2002;955 (1-2) 138- 152
PubMed
Halliday  GMMacdonald  VHenderson  JM A comparison of degeneration in motor thalamus and cortex between progressive supranuclear palsy and Parkinson's disease. Brain 2005;128 (pt 10) 2272- 2280
PubMed10.1093/brain/awh596

Figures

Place holder to copy figure label and caption
Figure.

Putative anatomic substrates for the nonmotor features of Parkinson disease. ANS indicates autonomic nervous system; DMNV, dorsal motor nucleus of the vagal nerve; LC, locus ceruleus; PPN, pedunculopontine nucleus; RBD, rapid eye movement behavior disorder; and RpN, raphe nuclei.

Graphic Jump Location

Tables

Table Graphic Jump LocationTable 1. Possible Clinicopathologic Correlates of Parkinsonian Tremor and Other (Later Stage) Extranigral Features and Treatments
Table Graphic Jump LocationTable 2. Early Premotor Features of PD

References

Doder  MRabiner  EATurjanski  NLees  AJBrooks  DJ Tremor in Parkinson's disease and serotonergic dysfunction: an 11C-WeregAY 100635 PET study. Neurology 2003;60 (4) 601- 605
PubMed
Braak  HDel Tredici  KRüb  Ude Vos  RAIJansen Steur  ENHBraak  E Staging of brain pathology related to sporadic Parkinson's disease. Neurobiol Aging 2003;24 (2) 197- 211
PubMed
Dickson  DWFujishiro  HDelleDonne  A  et al.  Evidence that incidental Lewy body disease is pre-symptomatic Parkinson's disease. Acta Neuropathol 2008;116 (1) 125- 128
Ross  GWPetrovitch  HAbbott  RD  et al.  Association of olfactory dysfunction with risk for future Parkinson's disease. Ann Neurol 2008;63 (2) 167- 173
Ross  GWAbbott  RDPetrovitch  H  et al.  Association of olfactory dysfunction with incidental Lewy bodies. Mov Disord 2006;21 (12) 2062- 2067
PubMed
Schenck  CHBundlie  SRMahowald  MW Delayed emergence of a parkinsonian disorder in 38% of 29 older men initially diagnosed with idiopathic rapid eye movement sleep behavior disorder. Neurology 1996;46 (2) 388- 393
PubMed
Stiasny-Kolster  KDoerr  YMöller  JC  et al.  Combination of ‘idiopathic’ REM sleep behaviour disorder and olfactory dysfunction as possible indicator for α-synucleinopathy demonstrated by dopamine transporter FP-CIT-SPECT. Brain 2005;128 (pt 1) 126- 137
PubMed10.1093/brain/awj322
Boeve  BFDickson  DWOlson  EJ  et al.  Insights into REM sleep behavior disorder pathophysiology in brainstem-predominant Lewy body disease. Sleep Med 2007;8 (1) 60- 64
PubMed
Uchiyama  MIsse  KTanaka  K  et al.  Incidental Lewy body disease in a patient with REM sleep behavior disorder. Neurology 1995;45 (4) 709- 712
PubMed
Postuma  RBLang  AEMassicotte-Marquez  JMontplaisir  J Potential early markers of Parkinson disease in idiopathic REM sleep behavior disorder. Neurology 2006;66 (6) 845- 851
PubMed
Abbott  RDRoss  GWWhite  LR  et al.  Excessive daytime sleepiness and subsequent development of Parkinson disease. Neurology 2005;65 (9) 1442- 1446
PubMed
Schuurman  AGvan den Akker  MEnsinck  KTJL  et al.  Increased risk of Parkinson's disease after depression: a retrospective cohort study. Neurology 2002;58 (10) 1501- 1504
PubMed
Shiba  MBower  JHMaraganore  DM  et al.  Anxiety disorders and depressive disorders preceding Parkinson's disease: a case-control study. Mov Disord 2000;15 (4) 669- 677
PubMed
Abbott  RDPetrovitch  HWhite  LR  et al.  Frequency of bowel movements and the future risk of Parkinson's disease. Neurology 2001;57 (3) 456- 462
PubMed
Abbott  RDRoss  GWPetrovitch  H  et al.  Bowel movement frequency in late-life and incidental Lewy bodies. Mov Disord 2007;22 (11) 1581- 1586
PubMed
Gao  XChen  HSchwarzschild  MA  et al.  Erectile function and risk of Parkinson's disease. Am J Epidemiol 2007;166 (12) 1446- 1450
PubMed
Remy  PDoder  MLees  ATurjanski  NBrooks  D Depression in Parkinson's disease: loss of dopamine and noradrenaline innervation in the limbic system [published online February 16, 2005]. Brain 2005;128 (6) 1314- 1322
PubMed10.1093/brain/awh445
Fumimura  YIkemura  MSaito  Y  et al.  Analysis of the adrenal gland is useful for evaluating pathology of the peripheral autonomic nervous system in Lewy body disease. Neuropathol Exp Neurol 2007;66 (5) 354- 362
Cools  R Dopaminergic modulation of cognitive function—implications for L-dopa treatment in Parkinson's disease. Neurosci Biobehav Rev 2006;30 (1) 1- 23
PubMed
Evans  AHPavese  NLawrence  AD  et al.  Compulsive drug use linked to sensitized ventral striatal dopamine transmission. Ann Neurol 2006;59 (5) 852- 858
PubMed
Black  KJHershey  THartlein  JMCarl  JLPerlmutter  JS Levodopa challenge neuroimaging of levodopa-related mood fluctuations in Parkinson's disease. Neuropsychopharmacology 2005;30590- 601
Clissold  BGMcColl  CDReardon  KRShiff  MKempster  PA Longitudinal study of the motor response to levodopa in Parkinson's disease. Mov Disord 2006;21 (12) 2116- 2121
PubMed
Alves  GLarsen  JPEmre  MWentzel-Larsen  TAarsland  D Changes in motor subtype and risk for incident dementia in Parkinson's disease. Mov Disord 2006;21 (8) 1123- 1130
PubMed
Williams  DRLees  AJ Visual hallucinations in the diagnosis of idiopathic Parkinson's disease: a retrospective autopsy study. Lancet Neurol 2005;4 (10) 605- 610
PubMed
Braak  HRüb  UJansen Steur  ENHDel Tredici  Kde Vos  RA Cognitive status correlates with neuropathologic stage in Parkinson disease. Neurology 2005;64 (8) 1404- 1410
PubMed
Colosimo  CHughes  AJKilford  LLees  AJ Lewy body cortical involvement may not always predict dementia in Parkinson's disease. J Neurol Neurosurg Psychiatry 2003;74 (7) 852- 856
PubMed
Bohnen  NIKaufer  DIIvanco  LS  et al.  Cortical cholinergic function is more severely affected in parkinsonian dementia than in Alzheimer disease: an in vivo positron emission tomographic study. Arch Neurol 2003;60 (12) 1745- 1748
PubMed
Poewe  W Treatment of dementia with Lewy bodies and Parkinson's disease dementia. Mov Disord 2005;20 ((suppl 12)) S77- S82
PubMed
Levy  G The relationship of Parkinson disease with aging. Arch Neurol 2007;64 (9) 1242- 1246
PubMed
Harding  AJBroe  GAHalliday  GM Visual hallucinations in Lewy body disease relate to Lewy bodies in the temporal lobe. Brain 2002;125 (pt 2) 391- 403
PubMed10.1093/brain/awf033
Goetz  CGWuu  JCurgian  LMLeurgans  S Hallucinations and sleep disorders in PD: six-year prospective longitudinal study. Neurology 2005;64 (1) 81- 86
PubMed
Cheng  AVTFerrier  INMorris  CM  et al.  Cortical serotonin-S2 receptor binding in Lewy body dementia, Alzheimer's and Parkinson's diseases. J Neurol Sci 1991;106 (1) 50- 55
PubMed
Mori  FTanji  KZhang  HKakita  ATakahashi  HWakabayashi  K α-Synuclein pathology in the neostriatum in Parkinson's disease. Acta Neuropathol 2008;115 (4) 453- 459
Joyce  JNRyoo  HLBeach  TB  et al.  Loss of response to levodopa in Parkinson's disease and co-occurrence with dementia: role of D3 and not D2 receptors. Brain Res 2002;955 (1-2) 138- 152
PubMed
Halliday  GMMacdonald  VHenderson  JM A comparison of degeneration in motor thalamus and cortex between progressive supranuclear palsy and Parkinson's disease. Brain 2005;128 (pt 10) 2272- 2280
PubMed10.1093/brain/awh596

Correspondence

CME
Meets CME requirements for:
Browse CME for all U.S. States
Accreditation Information
The American Medical Association is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. The AMA designates this journal-based CME activity for a maximum of 1 AMA PRA Category 1 CreditTM per course. Physicians should claim only the credit commensurate with the extent of their participation in the activity. Physicians who complete the CME course and score at least 80% correct on the quiz are eligible for AMA PRA Category 1 CreditTM.
Note: You must get at least of the answers correct to pass this quiz.
You have not filled in all the answers to complete this quiz
The following questions were not answered:
Sorry, you have unsuccessfully completed this CME quiz with a score of
The following questions were not answered correctly:
Commitment to Change (optional):
Indicate what change(s) you will implement in your practice, if any, based on this CME course.
Your quiz results:
The filled radio buttons indicate your responses. The preferred responses are highlighted
For CME Course: A Proposed Model for Initial Assessment and Management of Acute Heart Failure Syndromes
Indicate what changes(s) you will implement in your practice, if any, based on this CME course.
NOTE:
Citing articles are presented as examples only. In non-demo SCM6 implementation, integration with CrossRef’s "Cited By" API will populate this tab (http://www.crossref.org/citedby.html).
Submit a Comment

Multimedia

Some tools below are only available to our subscribers or users with an online account.

Related Content

Customize your page view by dragging & repositioning the boxes below.

Articles Related By Topic
Related Topics
PubMed Articles
JAMAevidence.com

The Rational Clinical Examination
Make the Diagnosis: Parkinsonism

The Rational Clinical Examination
Original Article: Does This Patient Have Parkinson Disease?