The Role Of Surgery In Pd4345
The use of surgery in PD dates back over 50 years. In the early 1950s, patients particularly those with severe tremor would on occasion be referred for ablative surgery usually to the contralateral thalamus. With the introduction of levodopa, surgical treatment fell from vogue. It is somewhat ironic that the widespread recognition of levodopa-induced complications prompted surgeons and clinicians to revisit the area of surgical intervention. Initially, this concentrated on lesion surgery usually in the form of pallidotomy which was shown to be successful particularly for levodopa-induced dyskinesias.
Age seems to be less critical in Vim DBS performed for disabling tremor. Recent studies have suggested that DBS of the pedunculopontine nucleus may be beneficial in improving axial stability. Assessment of a patient for DBS requires assessment by an experienced multi-disciplinary team.
Management Of Early Pd
After establishing a clinical diagnosis, it is vital to take time to explain the condition and its implications to the patient and relatives. It may take for some patients time to come to terms with and accept the diagnosis. Linking patients with PD nurse specialists and PD charitable organizations, if available locally, can be extremely helpful.
The timing when to start drug treatment in PD, particularly in the very early stages of the illness, when there may be little functional deficit can be difficult. The decision which should be made with full involvement of the patient is determined by the degree of physical impairment balanced against the complications that can be related to drug treatment. Of increasing importance is the issue of whether early treatment confers the potential for neuroprotection. This remains unresolved, despite a large number of in vitro, in vivo and human studies many of the latter using PET or SPECT imaging as surrogate markers of nigrostriatal dopaminergic function.
At present, therefore, there are no proven neuroprotective therapies with only symptomatic treatments available.
In patients with minimal or no disability, early treatment may still be initiated. One study has shown that self-reported health status using a Parkinson’s Disease Questionnaire -39 at initial consultation and for up to 18 months was worse in untreated PD patients, though the validity of the rating scale in this patient group has been questioned.
Peer Review Process And Process For Appeals
The Journal of Parkinson’s Disease operates a rigorous, timely, blinded peer-review process by experts in the field. Manuscripts submitted to the Journal of Parkinsons Disease will be assessed for suitability for publication in the journal by the Editors-in-Chief. Manuscripts that are deemed unsuitable may be rejected without peer review by the Editors-in-Chief and/or the Associate Editors, and the author will be informed as soon as possible. Manuscripts that are deemed suitable for peer review are forwarded to an Associate Editor with expertise in that area who then recruits appropriate anonymous referees for confidential review. Referee reports are then assessed by the Associate Editor, who makes a decision which is then subject to approval of the Editors-in-Chief. Once approved this decision is then conveyed to the author along with the referee’s anonymized reports.
The initial decision will be one of the following: rejection, acceptance without revision, or potentially acceptable after minor or major revisions. Revised manuscripts will be appraised by the Associate Editor, who may seek the opinion of referees before making a decision, which again is subject to approval of the Editors-in-Chief. Once approved, this decision is then conveyed to the author along with the anonymized referee’s reports. Once accepted manuscripts are normally published on-line without delay and appear in the next available print issue .
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Surgical Therapies With Transplantation And Gene Therapy
Cell transplantation is regarded as a potential future PD treatment. There have been trials using autologous and non-autologous cells. Human embryonic stem cells and induced pluripotent stem cells are few of the cells that have been included in these transplantation studies. One of the concerns with cell transplantation using stem cells is the ethical bounds that must be considered.
Since the first clinical trial in 1987 involving the transplantation of dopaminergic- neuron-rich human fetal mesencephalic tissue into PD patients striatums, more research has aimed to explore whether the grafted dopaminergic neurons will live and form connections in the brain, if the patients brain can harmonize and make use of the grafted neurons, and if the grafts can generate significant clinical improvement. Clinical trials with cell therapy intend to discover if there are long-lasting improvements following restoration of striatal DA transmission by grafted dopaminergic neurons. Experimental data from rodents and nonhuman primates show that fetal ventral mesencephalon intrastriatal grafted DA neurons demonstrate many morphological and functional characteristics of normal DA neurons. Significant improvements of PD-like symptoms in animal models have been demonstrated after successful reinnervation by the grafts. Dopaminergic grafts can reinnervate the striatum in the brain, restore regulated release of DA in the striatum, and can become functionally integrated into neural circuitries.
Pathogenesis Of Parkinsons Disease
A number of mechanisms have been implicated in PD pathogenesis, with -synuclein aggregation central to the development of the disease. Multiple other processes are thought to be involved, with several studies suggesting that abnormal protein clearance, mitochondrial dysfunction, and neuroinflammation play a role in the onset and progression of PD. However, the relationship between these pathways remains unclear.
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Anticholinergics For Early On
The first pharmacological agents used in PD therapy were anticholinergic drugs. They reduce the activity of acetylcholine by acting as antagonists at choline receptors, hoping to restore the balance between dopamine and acetylcholine levels that was disturbed by PD. These drugs have largely been replaced by L-DOPA and other centrally acting dopaminergic agonists, but they still remain available for use in the treatment of PD. Benztropine, biperiden, diphenhydramine, ethopropazine, orphenadrine, procyclidine, and trihexyphenidyl are included in this therapeutic class of drugs, though there is little pharmacokinetic information available on them because of their low plasma drug concentrations. Typically, anticholinergic drugs have a greater role in tremor-predominant PD and can be a monotherapy in early stages, but are usually done in adjunct with L-DOPA or other prescribed medications.
Research And Reviews In Parkinsonism
Editor-in-Chief: Dr Peter Hedera
Research and Reviews in Parkinsonism an international, peer reviewed, open access journal focusing on presenting current information about Parkinsonism related research, policy, phenomenology, literature, history and treatment. It reports on updates of various types of Parkinsonian syndromes as well as other movement disorders with overlapping features. The journal publishes review articles, historical reviews, original research articles, case reports, letters to the editor, clinical teaching cases, neuroradiology highlights, neuropathology highlights, and neuropsychiatry highlights.
This journal is a member of and subscribes to the principles of the Committee on Publication Ethics .
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Dopamine Dopamine Receptor And Dopamine Transporter Activity
A catecholamine neurotransmitter dopamine is secreted by the SN, hypothalamus and some other regions of the brain. TH synthesizes the dopamine precursor that is converted to dopamine by L-aromatic amino acid decarboxylase . In the brain, dopamine is used as the precursor of noradrenaline and adrenaline . Loss of dopaminergic neurons in the midbrain and SN of PD brains leads to the reduction of dopamine levels . The dopamine transporter controls dopamine levels by facilitating its reuptake back to the cytosol. However, free dopamine is toxic for neurons, since its oxidation creates poisonous reactive quinones. Therefore, the vesicular monoamine transporter 2 stores excess dopamine in vesicles. Thus, any change in dopamine or DAT levels may be an indicator of PD. Moreover, dopamine activates five types of receptors and the severity of PD is related to the decreased expression of the dopamine type 3 receptor , leading to more severe symptoms because of reduced dopamine signals . Therefore, D3R can be also considered as a potential biomarker for PD .
In another recent article a preclinical phase of PD is identified by analysis of dopamine metabolites in CSF. Low CSF concentrations of 3,4-dihydroxyphenylacetic acid and DOPA identify pre-clinical PD in at-risk healthy individuals .
Dysfunctional Protein Clearance Systems
There are two central protein clearance systems within cells responsible for the removal of dysfunctional proteins: the ubiquitin-proteasome system and the autophagy-lysosome pathway. The UPS is primarily responsible for breaking down abnormal proteins, and it does so by tagging them with ubiquitin and transporting them to the proteasome for degradation. The autophagy-lysosome pathway is divided into three constituents: macroautophagy, microautophagy, and chaperone-mediated autophagy . Briefly, in macroautophagy, intracellular components, including cytosolic proteins, are engulfed by the autophagosome, which then fuses with the lysosome, leading to the breakdown of its contents. On the other hand, in microautophagy, the lysosome alone engulfs and destroys cytoplasmic components. CMA is a more selective process, whereby molecular chaperones target specific proteins and transport them to the lysosome for degradation . Monomeric -synuclein is generally cleared by both the UPS and the autophagy-lysosome pathway , and damage in either of their machineries is implicated in the pathogenesis of PD by contributing to the accumulation of defective proteins, in particular soluble misfolded -synuclein .
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Diagnosis And Treatment Of Parkinson Disease: Molecules To Medicine
1Institute for Cell Engineering, 2Department of Neurology, 3Department of Neuroscience, and 4Department of Physiology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
Address correspondence to: Ted M. Dawson, Institute for Cell Engineering, Department of Neurology and Neuroscience, Johns Hopkins University School of Medicine, 733 North Broadway, BRB Suite 731, Baltimore, Maryland 21205, USA. Phone: 614-3359 Fax: 614-9568 E-mail: .
Find articles bySavitt, J.in: |PubMed |
1Institute for Cell Engineering, 2Department of Neurology, 3Department of Neuroscience, and4Department of Physiology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
Address correspondence to: Ted M. Dawson, Institute for Cell Engineering, Department of Neurology and Neuroscience, Johns Hopkins University School of Medicine, 733 North Broadway, BRB Suite 731, Baltimore, Maryland 21205, USA. Phone: 614-3359 Fax: 614-9568 E-mail: .
Find articles byDawson, V.in: |PubMed |
1Institute for Cell Engineering, 2Department of Neurology, 3Department of Neuroscience, and 4Department of Physiology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
Address correspondence to: Ted M. Dawson, Institute for Cell Engineering, Department of Neurology and Neuroscience, Johns Hopkins University School of Medicine, 733 North Broadway, BRB Suite 731, Baltimore, Maryland 21205, USA. Phone: 614-3359 Fax: 614-9568 E-mail: .
J Clin Invest.
What Is The Prognosis
Life expectancy is decreased in Parkinson disease , and medical treatments do not appear to alter mortality or delay the onset of nonmotor symptoms.114 Although progression is slower in patients with early-onset disease and there is longer absolute survival, this comes at the expense of increased years of life lost .24,115 Late-onset Parkinson disease is associated with more rapid disease progression and cognitive decline,116 which may be related to a lack of compensatory strategies against cell death.24 Data on the long-term outcomes and in the older population are lacking.117
Prognostic factors are summarized in Table 4. Patients with early-onset disease were slower to reach stage IIIV on the Hoehn and Yahr scale119 . The distribution of Hoehn and Yahr staging according to disease duration is listed in Appendix 8b. In the Rotterdam Study, Parkinson disease was associated with an increased risk of dementia and increased risk of death . When dementia prevalence was controlled for, risk of mortality was only slightly higher than among the general population.120
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Basics Of Parkinsons Disease
Parkinsons disease , or paralysis agitans, is a common neurodegenerative condition, which typically develops between the ages of 55 and 65 years. This disease was first named and described by James Parkinson in 1817. The progression of this disease is gradual and prolonged. It has a plausible familial incidence, although the estimates of these occurrences are low and usually sporadic. This disease is organized into two classifications: genetic and sporadic. Genetic PD follows Mendelian inheritance. Sporadic PD, which accounts for about 90% of all Parkinsons cases, is a more complex category in which the pathogenic mechanisms that underlie it are not yet fully understood. Nonetheless, it is known that the byzantine interactions of genetic and environmental influences play roles in the determination of sporadic PD. Several subtypes of PD exist. Each has its own set of causative factors and susceptibilities, pathology, and treatment courses. General risk factors, symptoms, and pathology will be discussed first, before addressing some of the subtypes.
Neuropathology Of Parkinsons Disease
Macroscopically, the brain in idiopathic PD is often unremarkable with mild atrophy of the frontal cortex and ventricular dilation in some cases. The main distinctive morphological change in the PD brain is observed in transverse sections of the brainstem, where almost all cases present with loss of the darkly pigmented area in the substantia nigra pars compacta and locus coeruleus. This pigmentation loss directly correlates with the death of dopaminergic neuromelanin-containing neurons in the SNpc and noradrenergic neurons in the locus coeruleus . Cell death in the SNpc is mostly restricted to a specific group of neuromelanin-containing dopaminergic neurons, namely the A9 neurons, while other neuronal and glial cell types are largely spared .
Coronal section at the level of the substantia nigra pars compacta in a control and a PD brain stained by hematoxylin and eosin. In both sections, the dark brown cells are the neuromelanin-containing dopaminergic neurons.
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What Tests Or Investigations Are Available To Help With Diagnosis
Parkinson disease is a clinical diagnosis, and magnetic resonance imaging may be used only to exclude other causes, as listed in Appendix 1. Advancements in neuroimaging studies, including transcranial Doppler ultrasonography,51 positron emission tomography , single-photon emission computed tomography , morphometric MRI studies, tractography, functional MRI and perfusion imaging are being used to differentiate idiopathic Parkinson disease from other parkinsonian disorders.52,53
Radionuclide imaging modalities like PET and SPECT, using a dopamine transporter ligand, have become the best approach to assess dopamine metabolism and deficiency. Tracer uptake is reduced maximally in the posterior or dorsal striatum and is asymmetric in Parkinson disease.52,53
A subgroup of patients suspected of having new-onset Parkinson disease will have no evidence of dopaminergic deficit on dopamine transporter SPECT and fluorine-18 fluoro-L-dopa PET imaging scans.54 In this group of patients, progression of disease, by imaging or clinical measures, is minimal, as is their likelihood of developing idiopathic Parkinson disease.54 However, a few may eventually be diagnosed with Parkinson disease, based on clinical progression, imaging and genetic evidence and a positive response to levodopa.55
There are currently no biomarkers of proven clinical utility. Cerebrospinal fluid levels of -synuclein may predict cognitive decline but do not correlate with motor progression.56
How Is Parkinson Disease Treated
Dopaminergic medications are the mainstay of symptomatic therapy for motor symptoms in Parkinson disease. The mechanisms of action, starting and target doses and adverse effects of medications are summarized in Appendix 2, available at www.cmaj.ca/lookup/suppl/doi:10.1503/cmaj.151179/-/DC1. Discovered in the 1960s, levodopa was the first symptomatic treatment for Parkinson disease, followed by the availability of dopamine agonists and monoamine oxidase B inhibitors. Until recently, the decision regarding which treatment to initiate has been debated. There is no one medication that is recommended for treatment initiation currently, but factors such as symptom severity, embarrassment, ability to perform activities, cost and patient preference should be taken into account. If symptoms are very mild, the patient may choose not to begin therapy.34,57
Because patients with early-onset disease are more likely to develop levodopa-induced abnormal movements , dopamine agonists are often introduced as initial treatment however, this early advantage of dopamine agonists over levodopa diminishes over time .34 There is also some controversial evidence for neuroprotection with the monoamine oxidase B inhibitor rasagiline at the 1 mg daily dose 58 however, its cost is not covered in most provinces and may require application to the exceptional access program, as is done in Ontario.
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What Has Changed In The Treatment Of Advanced Parkinson Disease
In advanced Parkinson disease, the efficacy of levodopa can decline and fluctuate throughout the day switching between on and off medication periods.92 The motor and nonmotor fluctuations mirror those seen in levodopa plasma concentrations resulting from levodopas short half-life.93 Providing continuous dopaminergic stimulation is the goal of treating fluctuations in patients with advanced Parkinson disease.9496 We now have surgical options, including deep brain stimulation and levodopacarbidopa intestinal gel, to provide treatment to such patients. Currently, deep brain stimulation has the highest level of evidence with the largest number of randomized controlled trials.97 Emerging therapies currently being studied in Parkinson disease are listed in Appendix 7, available at www.cmaj.ca/lookup/suppl/doi:10.1503/cmaj.151179/-/DC1.
Symptomatic Treatment Of Motor Symptoms
Levodopa
A majority of patients with PD require levodopa therapy within 2 years of symptom onset. Levodopa, the most effective drug in the treatment of PD, is almost always combined with carbidopa or benserazide, aromatic acid decarboxylase inhibitors that prevent its peripheral metabolism and markedly reduce the risk of nausea. Increasing the ratio of carbidopa:levodopa from the current standard 1:4 has been shown to increase on time without dyskinesia and reduce off time.
The global antiparkinsonian efficacy of levodopa is so predictable that a positive therapeutic response is used to support the diagnosis of PD. Adverse effects of levodopa include nausea and vomiting, orthostatic hypotension, sedation, confusion, sleep disturbance, hallucinations and dyskinesias. There are many different types of dyskinesia but peak-dose chorea or stereotypy and wearing off dystonia are most common. About half of the patients experience wearing off, and a third experience dyskinesias within 2 years after initiation of levodopa therapy. Latency from ingestion of levodopa to observable therapeutic benefit can be shortened by taking levodopa on an empty stomach , avoiding or reducing protein intake, or by crushing the levodopa tablet and mixing it with a carbonated beverage.
Other drugs
Besides levodopa, there are many other types of medications available for the treatment of PD-related motor symptoms: anticholinergics, amantadine, MAOIs, COMTIs, dopamine agonists and istradefylline.
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