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REVIEW ARTICLE
Year : 2018  |  Volume : 66  |  Issue : 7  |  Page : 26-35

Parkinson's disease: A review


Department of Neurology, All India Institute of Medical Sciences, New Delhi, India

Date of Web Publication1-Mar-2018

Correspondence Address:
Dr. Vinay Goyal
Department of Neurology, All India Institute of Medical Sciences, New Delhi
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0028-3886.226451

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 » Abstract 


Parkinson's disease is a common movement disorder seen in neurological practice, but the diagnosis and management is challenging. The diagnosis is clinical and sometimes difficult, considering a large number of motor and non-motor symptoms in PD patients. The medical management of PD patients is difficult, as choices of drugs are limited and levodopa is the mainstay of treatment. However, levodopa-induced dyskinesia (LID) is commonly seen in Parkinson's disease patients treated with levodopa. This side effect is usually encountered after a long duration of treatment, but occasionally, this may be seen even after a few days or months of treatment. Different types of surgical approaches, including unilateral pallidotomy and deep brain stimulation, have given very good results in PD patients, who cannot be managed by medications alone.


Keywords: Deep brain stimulation, dopaminergic drugs, Parkinson's disease
Key Message: This review addresses the epidemiological features, pathophysiology, genetics, pathology, and the clinicoradiological presentations in patients suffering from Parkinson's disease and also studies the therapeutic options available in treating this progressive disease.


How to cite this article:
Radhakrishnan DM, Goyal V. Parkinson's disease: A review. Neurol India 2018;66, Suppl S1:26-35

How to cite this URL:
Radhakrishnan DM, Goyal V. Parkinson's disease: A review. Neurol India [serial online] 2018 [cited 2018 Dec 16];66, Suppl S1:26-35. Available from: http://www.neurologyindia.com/text.asp?2018/66/7/26/226451




Parkinson's disease (PD) is a chronic progressive neurodegenerative disorder characterized by early prominent death of dopaminergic neurons in the substantia nigra pars compacta (SNpc) and wide spread presence of alpha synuclein (aSyn), an intracellular protein. Dopamine deficiency in the basal ganglia leads to classical Parkinsonian motor symptoms viz, bradykinesia, tremor, rigidity and later postural instability. PD is also associated with non-motor symptoms, which may precede motor symptoms by more than a decade. These non-motor symptoms become troublesome symptoms in the later stages of PD. Currently, the mainstay of PD management is pharmacological therapy; however, these symptomatic therapies have major limitations in advanced disease. Many disabling features develop later in the course of the disease including non-motor symptoms, dopamine resistant motor symptoms and motor complications of long-term dopamine therapy. Although there have been remarkable advances in the medical and surgical treatment for PD, definitive disease modifying therapy is lacking. However, researchers are hopeful that they will be able to identify the potential targets for disease modification. In this review, we will be discussing the epidemiology, clinical features, pathophysiology, diagnosis and management (medical and surgical) of PD. Experimental therapies have so far yielded only limited test results and will not be discussed here.

Epidemiology

The incidence and prevalence of PD increases with advancing age, being present in 1% of people over the age of 65 years.[1] Early-onset Parkinson's disease (EOPD) is defined as the onset of parkinsonian features before the age of 40 years. It accounts for 3-5% of all PD cases. It is classified into the 'juvenile' (occurring before the age of 21 years) and 'young-onset' PD (YOPD, occurring in the age range of 21- 40 years).[2] PD is twice as common in men than in women in most populations.[3],[4] A protective effect of female sex hormones is observed. The presence of gender - associated genetic mechanisms or/and gender -specific differences in exposure to environmental risk factors might explain this male preponderance.[3],[4]

There is no homogenous and large epidemiological data on PD from India. Razdan et al., reported a crude prevalence rate of 14.1 per 100,000 amongst a population of 63,645 from rural Kashmir in the northern part of India. The prevalence rate over the age of 60 years was 247/100,000.[5] A low prevalence rate of 27/100,000 was reported from Bangalore, in the southern part of India, and 16.1/100,000 from rural Bengal, in the eastern part of India.[6],[7] Bharucha et al., reported a high crude prevalence rate of 328.3/100,000 among a population of 14,010 Parsis living in colonies in Mumbai, Western India.[8]


 » Pathophysiology Top


Genetics of PD

Genetic forms of PD represent only 5–10% of all cases.[9],[10] Presence of family history, early onset of disease and specific clinical features (e.g., dystonia as a presenting symptom) arouse suspicion of the presence of the genetic form of the disease in a patient. A genetic basis can be seen in >10% of YOPD individuals and the proportion of genetically defined cases rises to >40% if the onset of disease is before 30 years of age.[11],[12] The major genes identified and proved to be causal in PD include Parkin (PARK2), Leucine rich repeat kinase2 (LRRK2/PARK8), Alpha synuclein (SNCA-PARK1/PARK4), PTEN induced putative kinase 1 (PINK1/PARK6), DJ1 (PARK 7), ubiquitin C-terminal hydrolase like 1 (UCH-L1), and ATPase type 13A2 (ATP13A2).[9],[10],[13]


 » Genetics of Pd in India Top


Mutations reported in the Parkin gene are the highest and vary from 1.96% to 39.1% among Indian case series.[14] Mutations are absent in SNCA, and less frequent in DJ1, PINK1 and LRRK2.[14] Mutations in the Parkin gene have been implicated to cause the autosomal recessive (AR) early onset PD and vary considerably between subjects from different geographical locations in India.[15],[16],[17],[18],[19]

Chaudhary et al., in 2006 observed that Parkin mutations accounted for 14.3% cases of familial PD, 6.9% cases of young onset (age of onset ≤40 years), and 5.9% cases of late onset (age of onset ≥41 years) sporadic PD.[16] Padmaja MV et al., in 2012 reported Parkin mutations in 68% of the early onset PD cases in a study from the southern part of India.[19] Differentiating Parkin positive young onset PD patients from Parkin negative patients on clinical features alone is not possible.[9],[10]

DJ-1 mutations (seen in AR Parkinsonism) are responsible for early onset of PD symptoms with a benign course. These mutations are characterized by a good response to levodopa and are usually associated with the presence of dystonia. The prevalence of DJ1 mutations (AR) in patients with PD is modest (~5%) in the Indian population.[20] Two other Indian studies looked at the prevalence of DJ1 mutations in PD patients.[21],[22] One study reported a prevalence of 3.9% of the DJ1 variants,[21] while another study failed to identify any pathogenic mutations.[22]

The LRRK 2 (autosomal dominant [AD] Parkinsonism) is the most common cause of 'familial' as well as 'sporadic' PD globally, with the frequency of mutations being 5-7% in patients with a family history of PD.[23] LRRK2 mutations, however, have been less frequently seen in India.[24],[25],[26],[27],[28] The most frequent and best-studied LRRK2 mutation is the substitution of glycine by serine at 2019 position (c.6055G>A).[29] The study by Vijayan B et al., could not find any contribution by G2019S mutation in the pathogenesis of PD.[25] Punia et al., saw similar results in a previous study from the northern part of India (composed of a heterogeneous population), which reported LRRK2 mutations in <0.1% of PD cases.[27]

A point mutation of the SNCA gene causes early onset of PD (AD), and its over-expression causes the development of PD symptoms at a later age in the fourth or fifth decades in the affected members.[9],[10] SNCA mutations, however, rarely contribute to PD in India.[24],[30] A limited study with 100 PD cases from north Karnataka, India, suggested that SNCA mutations might be population specific and, therefore, might not be playing a causal role in all the populations studied.[31] The PINK1 gene, coding for a mitochondrial complex, has been implicated in the causation of an AR form of Parkinsonism.[32] The contribution of PINK1 variants in the causation of PD is limited in India.[33],[34] Tamali Halder et al., observed that 1.8% (2/106) patients suffering from PD in northern India harbor the PINK1 variants.[34]

In 2016, Sudhaman et al., discovered a novel frame shift mutation in the podocalyxin- like (PODXL) gene as a likely cause of early onset Parkinsonism (AR) in one Indian family, in whom the test for mutations in the Parkin, PINK1 and DJ1 genes was negative.[35] New mutations are being identified on a daily basis and have added to the spectrum of causation of genetic PD. However, the contribution of genetic testing in the management of PD is limited and there is no influence of positive genetic testing on the decision-making regarding treatment.


 » Neuropathology Top


The pathophysiology of PD involves loss or degeneration of the dopaminergic neurons in substantia nigra pars compacta (SNpc) and the accumulation Lewy bodies, which are abnormal intracellular aggregates containing proteins, like alpha-synuclein (aSyn) and ubiquitin.[36],[37] About 60-70% of neurons in SNpc are lost before symptoms occur.[38] Research has revealed that the pathogenic process in PD involves regions of the peripheral and central nervous system in addition to the dopaminergic neurons of the SNpc. Lewy body pathology starts in cholinergic and monoaminergic brainstem neurons and in the neurons of the olfactory system, but involves limbic and neocortical brain regions with disease progression.[39],[40] Loss of dopaminergic neurons that was initially restricted to SNpc becomes more widespread by the time end-stage disease has been established.[41],[42]

Motor circuit changes in PD

Selective loss of dopaminergic neurons in the striatum causes impairment of motor control in persons with PD. The motor circuit of PD consists of corticostriatal projections from the primary motor cortex, supplementary motor area, cingulate motor cortex and premotor cortex, terminating on the dendrites of the striatal medium spiny neurons.[43],[44] The direct pathway is a monosynaptic connection between the medium spiny neurons that express dopamine D1 receptors and GABAergic (gamma amino butyric acid-ergic) neurons in the globus pallidus internus (Gpi) and the substantia nigra pars reticulata (SNpr). The 'indirect' pathway originates from medium spiny neurons that express D2 receptors, which project to the globus pallidus externus (Gpe), and reaches the Gpi via the subthalamic nucleus (STN) as a glutamatergic relay. Through these two pathways, the striatal dopaminergic tone regulates the GABAergic output activity of the basal ganglia. There is reduction in the D1 mediated direct pathway activity and an increase in the D2 mediated indirect pathway activity, resulting in a net increase in the firing rate of basal ganglia output neurons (GABA), which over-inhibit downstream thalamocortical and brainstem areas.[43],[44]

Changes in cerebellar activity and in the interaction between the basal ganglia and cerebellum contribute to the pathophysiology of tremor in PD.[45] Abnormalities of balance and gait are due to dysfunction of the basal ganglia output via projections into the midbrain locomotor region (pedunculo-pontine and cuneiform nuclei).[46]

Gut and PD

Parasympathetic nerves and enteric nervous systems are among the structures earliest affected by the aSyn pathology. Dysfunction of the brain-gut-microbiota axis in PD may be associated with non-motor symptoms that are evident before the classical motor symptoms, supporting the hypothesis that the pathological process spreads from the gut to the brain.[47] Gut microbiomes play an important role in regulating movement disorders, and alterations in the microbiota might be a risk factor for PD. Sampson et al., using mice that overexpress aSyn, reported that alterations in the gut microbiota were required for motor deficits, microglial activation, and aSyn pathology to develop.[48] Antibiotic treatment ameliorated, while microbial re-colonization promoted the pathophysiology in adult animals, suggesting that postnatal signaling between the gut and the brain modulates the onset and course of the disease.[48] Oral administration of specific microbial metabolites [e.g., short chain fatty acids (SCFA)] to germ-free mice promoted the development of neuroinflammation and motor symptoms. Investigations have shown that alterations in the gut microbiome is related to several clinical features. A recent Finnish study has shown that alterations in the microbiota composition, in particular, the abundance of Enterobacteriaceae is positively associated with the severity of postural instability and gait difficulty in PD patients.[49] Keshavarzian et al., and Unger et al., observed that faeces derived from patients with PD contained less short chain fatty acids (SCFA) including butyrate, that produce bacteria that could exert anti-inflammatory properties.[50],[51] An increase in the intestinal permeability and the dysfunction in the intestinal symbiosis have also been proposed as the mechanisms responsible for the development and progression of PD.[52] Recently, Hill-Burns et al., observed significantly altered abundance of several taxa in 197 patients with PD. They demonstrated the independent effects of PD medications on these microbiomes, thereby providing further leads in the pathophysiology and treatment of PD.[53]


 » Clinical Diagnosis and Natural History Top


Parkinson's disease is defined clinically by the presence of bradykinesia in combination with at least one more manifestation: muscular rigidity, rest tremor or postural instability (the latter being a feature of the more advanced form of the disease).[54] Motor symptoms starts unilaterally, and asymmetry persists throughout the course of the disease. Non-motor symptoms are seen in a large proportion of patients. Some of these non-motor symtpoms can antedate the onset of cardinal motor symptoms by years.[55] These non-motor symptoms include sleep disorders [for example, frequent waking, rapid eye movement sleep behavior disorder (RBD), and day time somnolence], hyposmia, disturbance in autonomic function [orthostatic hypotension, urogenital dysfunction, and constipation], cognitive impairment, mood disorders and pain.[55] The Sydney Multicentre Study of Parkinson's disease reported dementia (83%), hallucinosis (74%), symptomatic hypotension (48%), constipation (40%) and urinary incontinence (20%) in 71% of patients with PD who had survived for >20 years after the onset of the disease.[56] Freezing of gait, postural instability and falling and choking were reported in 81%, 87% and 48% of the patients, respectively.[56]

Alhough there is no consensus regarding the classification of PD subtypes, clinical observations suggest the existence of two major subtypes: tremor-dominant PD (with a relative absence of other motor symptoms), and non-tremor-dominant PD (which includes phenotypes described as the akinetic-rigid syndrome and the postural instability gait disorder, PIGD). Tremor-dominant PD is often associated with a slower rate of progression and less functional disability than the non-tremor-dominant Parkinson's disease.[57]

Almost 90% patients with PD experience non-motor symptoms during the course of their illness that usually do not respond well to dopamine therapy.[58] Mood disorders and constipation almost double an individual's risk for developing Parkinson's disease in the later years.[59] Idiopathic RBD carries a high risk for the development of PD and other α-synucleinopathies.[60] The average latency between the onset of RBD and the occurrence of Parkinsonian motor symptoms is 12–14 years.[61]

Autonomic symptoms (mentioned above) increase with a higher age, with disease severity, and with higher doses of dopaminergic medications. Urinary symptoms include urgency, frequency, nocturia, and urge incontinence, with urinary storage problems being commoner than voiding difficulties. Urinary symptoms are more frequent and occur earlier in multisystem atrophy (MSA) when compared to PD.[62] Painful sensory symptoms are seen in two-third of PD patients and are thought to be due to abnormal nociceptive processing.[62]

There is a six-fold increased risk for dementia (subcortical type) in patients with PD and this occurs later in the course of the disease course.[63] Upto 60% of patients with PD develop dementia within 12 years of its diagnosis.[63] Hyposmia occurs in approximately 90% of patients with an early-stage PD and antedates the typical motor symptoms by several years.[64] Occurrence of hyposmia may predict a higher risk of developing PD, and olfactory testing might help in differentiating PD from other parkinsonian syndromes.


 » Imaging Top


Early PD is a diagnostic challenge with the existence of wide differential diagnoses that consists of disease that are not associated with nigral degeneration or striatal dopamine deficiency. The commonly used UK Parkinson's Disease Society Brain Bank (UKPDSBB) Clinical Criteria has a diagnostic accuracy of only about 80% at the first visit following the development of early PD in a patient.[65] Thus, functional imaging is necessary to confirm the clinical diagnosis and to understand the underlying pathophysiology.

123I-ioflupane single-photon emission computed tomography [SPECT] (also known as DaTscan) is useful to assess the density of the presynaptic dopaminergic terminals within the striatum as it helps to differentiate PD from disorders that exist without the presence of presynaptic dopaminergic terminal deficiency.[66],[67]

18 F-DOPAL-6-fluoro-3, 4-dihydroxyphenylalnine (18 F-DOPA) positron emission tomography (PET) scan assesses the presynaptic dopaminergic integrity and accurately reflects the monoaminergic disturbances in PD. A retrospective analysis of 27 patients who underwent 18 F-DOPA PET scan for motor symptoms suspicious of PD showed its sensitivity as being 95.4% (95% confidence intervals [CI], 100%-75.3%), specificity 100% (95% CI: 100%-59.0%), positive predictive value (100% (95% CI, 100%-80.7%), and negative predictive value 87.5% (95% CI, 99.5%-50.5%).[68]

[123 I] N-ω-fluoropropyl-2β-carbomethoxy-3β-(4-iodophenyl) nortropane (FP-CIT) is a selective and potent dopamine transporter imaging [DAT] agent. Correlation between the values obtained on FP-CIT single photon emission computed tomography (SPECT) and F-DOPA PET for striatal uptake in patients with different stages of PD has been proven.[69],[70] Dopamine transporters get downregulated as an early response to reduction in the amount of endogenous dopamine concentration and this results in a decreased striatal binding of FP-CIT in the early phases of PD. FP-CIT might, therefore, be more sensitive than the F-DOPA scan for detecting early striatal dopaminergic deficits. A study compared the sensitivity and specificity of the contralateral striatal and putaminal uptake based on the findings of FP-CIT SPECT and F-DOPA PET in patients with Parkinson's disease and healthy controls and found it to be 100% in the early phase of the disease. When only caudate uptake was considered, the specificity remained 100% for FP-CIT but reduced to 90% for F-DOPA, while the sensitivity was 91% for both the scanning techniques.[71] However, techniques that rely solely on dopamine imaging are not sufficient to diagnose Parkinson's disease because they do not reliably distinguish PD from other parkinsonian syndromes associated with nigral degeneration, such as atypical parkinsonism.

The standard magnetic resonance imaging (MRI) has a marginal role in establishing the diagnosis of PD; however, the high and ultra-high-field (7 Tesla) MRI combined with advanced techniques, such as diffusion tensor imaging, are being explored for determining an early diagnosis of Parkinson's disease.[72] MRI helps to identify patients with symptomatic parkinsonism, and also helps to show specific changes in the basal ganglia and infra-tentorial structures in patients with atypical Parkinsonism.[73] Myocardial sympathetic denervation, assessed with PET or SPECT using noradrenergic tracers, is seen in PD, but not in patients with atypical parkinsonism or other PD mimics.[74]


 » Cerebrospinal Fluid (CSF) and Blood Tests Top


Currently, there is no clinically useful CSF based test for the diagnosis of PD. There were several studies that assessed the levels of proteins in CSF (e.g., the levels of different α-synuclein species) but the sensitivities and specificities of these tests have been low.[75] Though, lower plasma level of apolipoprotein A1 often correlates with a greater severity of motor symptoms, its utility as a blood biomarker is not established till date.[76]

The major roadblock in PD research is absence of good biomarkers with a high sensitivity and specificity to diagnose the disease in the early or even the prodromal stage; and, no single measure currently fulfills all the necessary criteria for a biomarker in PD.[77] Disease modifying therapies would be most effective if patients are diagnosed and treated during this prodromal period. The possible clinical markers include RBD diagnosed by polysomnography, and olfactory dysfunction measured by standard methods, such as the University of Pennsylvania's smell identification test.[61]

Pharmacologic management

The major objective of PD research is to develop disease-modifying therapy that can slow or stop the neurodegenerative process. However, there is no existing definitive disease-modifying therapy to achieve this aim.

Dopaminergic therapy

The American Academy of Neurology (AAN) recommends initiating one of the following available drug therapies once the patients develop functional disability.[78] The medical therapies available for treatment of motor symptoms include levodopa/carbidopa, dopamine agonists (both ergot and non-ergot types), monoamine oxidase-B (MAO-B) inhibitors, injectable dopamine agonist (apomorphine), catechol-O-methyltransferase (COMT) inhibitors, N-methyl-D-aspartate (NMDA) receptor inhibitors, and anti-cholinergics. In the later stages of PD, drug delivery can be supplemented via alternative routes [79],[80],[81],[82] (e.g., intrajejunal infusions, subcutaneous injections or transdermal patches). Continued motor fluctuations and dyskinesias indicate the patient's candidacy for deep brain stimulation (DBS).

Dopaminergic therapy is highly effective in bradykinesia and rigidity but monoamine MAO B inhibitors are only moderately effective. Dopamine agonists and levodopa help to reduce disease progression and disability. Tremor responds to anticholinergic drugs like trihexyphenidyl but has a poor and inconsistent response to dopamine replacement therapy.[83],[84]


 » Levodopa and Novel Levodopa Formulations Top


The mechanism for major motor symptoms in PD is the depletion of striatal dopamine due to loss of dopaminergic neuron in the SNpc. Administration of levodopa to substitute striatal dopamine was a major breakthrough in the treatment of PD, and since then, multiple additional targets for dopaminergic therapies have been identified. Levodopa is considered as gold standard therapy and almost all patient require this particular treatment during the course of their illness.[85]

Long-term use of levodopa is complicated by motor fluctuations and dyskinesias. Mechanisms underlying these motor complications are still unclear. One accepted hypothesis for this manifestation is the involvement of both presynaptic and postsynaptic mechanisms that eventually lead to non-physiological pulsatile striatal dopamine receptor stimulation, causing various maladaptive neuronal responses.[86],[87] Erratic drug delivery due to the short half-life of levodopa, as well as variability in its absorption and blood–brain barrier transportation also play an important role in the development of motor complications.[82]

Levodopa bioavailability can be improved either by developing more effective oral formulations (e.g., sustained release formulations) or by devising innovative routes of administration (e.g., intestinal infusion, transcutaneous administratin via mini pumps or by inhalation). RYTARY/IPX066 is a novel levodopa-carbidopa (LD/CD) oral formulation combining the immediate-release and extended-release LD/CD. This has been approved in the USA and the European Union. IPX066 is composed of LD/CD micro-beads designed to dissolve at various rates that allows for a quick absorption and sustained levodopa release over an extended period of time. Studies have shown that IPX066 administration improved the symptoms in patients with both early and advanced PD.[88],[89],[90],[91],[92],[93] Significant improvement in the unified Parkinson's disease rating scale (UPDRS) scores has been reported without the development of worsening troublesome dyskinesias, using this preparation when compared to other levodopa formulations.[88],[89],[90],[91],[92],[93]

Levodopa-carbidopa intestinal gel (LCIG) is an approved therapy for inpatients with advanced PD. LCIG is delivered continuously by a percutaneous endoscopic gastrojejunostomy tube (PEG-J), through a portable infusion pump. It reduces L-dopa-plasma level fluctuations and thereby decreases the motor complications.[80],[81],[94] Recently, researchers are evaluating the 'accordion pill' (AP09004), an extended release LD/CD formulation with gastroretentive properties.[95],[96],[97] Other levodopa formulations currently active in studies include ND-0612, ODM-101, CVT-301 and cyclops. ND-0612 is a proprietary liquid formulation of LD/CD that enables subcutaneous administration via a small patch-pump device; and, ODM-101is a new oral formulation of levodopa/carbidopa/entacapone that contains a higher amount of carbidopa (65 or 105 mg).[98],[99],[100] CVT-301 and cyclops are levodopa inhalation powders. As they possess a rapid onset of action, they are promising candidates for the treatment of PD.[101],[102]

Although, the highest levels of symptomatic relief is provided by levodopa, to delay the ensuing complications, MAO-B inhibitors/dopamine agonists can be considered as the initial therapy. A randomized trial of newly diagnosed PD patients failed to show the long-term benefit of levodopa sparing therapy.[103] This study, however, had limitatons characterized by a lack of generalizability, as patients <60 years of age, who were at a high risk of developing dyskinesias, were not well represented.[104]

Dopamine agonists

Dopamine receptors mainly target the D2 receptor family. The initial members of this family of drugs were ergoline derivatives. Ergoline drugs raised cardiac and pulmonary safety concerns and the currently used agents are all non-ergoline drugs, e.g., pramipexole, ropinirole, apomorphine, piribedil, rotigotine. Dopamine agonists induce less pulsatile striatal dopamine receptor stimulation than levodopa and can markedly reduced the risk of motor complications when they are being used as initial monotherapy.[84],[105],[106]

Apomorphine has both D1 and D2 receptor activity and a potency equal to that of levodopa.[66] Continuous subcutaneous apomorphine infusion reduces the motor response fluctuations and levodopa induced dyskinesias.[107] Another drug, rotigotine, is available as a transdermal patch formulation that permits a continuous drug delivery.[79]

Both levodopa and dopamine agonists are associated with nausea, daytime sleepiness and edema, but the adverse effects are more frequent with dopamine agonists. Dopamine agonists are known to cause impulse control disorders and drug induced hallucinations (especially in elderly people with cognitive impairment), and therefore, they are better avoided in the high-risk groups.

MAO B inhibitors

MAO B inhibition leads to an increase in the synaptic dopamine concentration and in symptomatic efficacy. Selegiline, a selective irreversible MAO B inhibitor, has proven its efficacy as an adjunct to levodopa since the 1970s.[108] Results from the MONOCOMB study showed that selegiline monotherapy in early-phase PD retarded the progression of the disease. In advanced PD, selegiline had levodopa-sparing qualities and was reasonably well tolerated on long-term usage.[109] In a recent trial conducted in Japanese patients with early PD, selegiline monotherapy significantly reduced UPDRS part I + II + III scores.[110]

Rasagiline, another irreversible MAO B inhibitor, is a well-known add-on therapy in patients with motor fluctuations.[105] A head-to-head 3-year retrospective case control study, analyzing the efficacy of MAO B inhibitors in PD, reported an equal efficacy in controlling motor symptoms in PD patients on optimized therapy.[111] MAO B inhibitor therapy was associated with a significant reduction in the levodopa requirements and a lower frequency of dyskinesias.[111]

Safinamide is a reversible MAOB inhibitor with antiglutaminergic properties. Safinamide gives enhanced control over motor symptoms in advanced PD and improves the quality of life.[112] In a recent randomized control trial, safinamide, when used as an adjunct to levodopa, improved the ON time without causing troublesome dyskinesias, and reduced the incidence of 'wearing off' phenomenon.[113]

Catecohol-O-methyl transferase (COMT) inhibitors

Current levodopa preparations contain carbidopa or benserazide to prevent peripheral metabolism of dopamine and, therefore, these drugs enhance the bioavailability of the former medication. This shifts the peripheral metabolism of levodopa to a secondary pathway that involves COMT. Inhibition of the COMT pathway will further increase the bioavailability and the half-life of levodopa, thus, helping patients with motor fluctuations.[114] Triple therapy with levodopa/carbidopa/COMT inhibitor increases the ON time, reduces the OFF time, and significantly improves the quality of life.[115] Use of tolcapone is restricted due to its side effects. Entocapone, a safer alternative, is currently available but is less efficacious. In phase II trials, nebicapone has been found to be more efficacious than entacapone and is safer than tolcapone.[116] Opicapone, in a once-a-day oral dose regimen, has also been proven to reduce the OFF time and to increase the ON time without troublesome dyskinesias, in patients suffering from advanced PD.[117]


 » Non-Dopaminergic Pharmacological Targets Top


Symptoms of late stage PD (both motor and nonmotor) respond poorly to dopaminergic therapy. The reason may be abnormalities in other non-dopaminergic neurotransmitters like acetylcholine, glutamate, norepinephrine or serotonin.[118] Motor fluctuations, levodopa induced dyskinesias, freezing of gait, postural instability and falls, treatment-resistant tremor, swallowing and speech disturbances are among the symptoms that require treatment with non-dopaminergic agents.

Acetylcholine deficiency, due to degeneration of cholinergic neurons, leads to dementia, gait abnormalities and falls.[119] The trial of donepezil instituted for treatment of falls is related to the hypothesis of the existence of an abnormal cholinergic system in PD that is responsible for the frequent falls.[120] Rivastigmine, a cholinesterase inhibitor, is used for PD associated dementia.[121] The usefulness of rivastigmine in treating gait abnormalities and frequent falls is being evaluated.[122]

Depression in patients with PD responds to all types of antidepressant medications and there is limited evidence to recommend tricyclic antidepressants over selective serotonin reuptake inhibitors. The role of noradrenergic medications needs to be firmly established in clinical trials.[123] Psychotic symptoms in Parkinson's disease respond well to clozapine.[123],[124] Apart from quetiapine, all other atypical neuroleptics worsen Parkinsonism by blocking the striatal dopamine D2 receptors. A serotonergic effect of clozapine in treating psychosis is strongly supported by the recent positive results using the 5hydroxytryptamine 2A (HT2A) inverse agonist, pimavanserin.[125]

Amantidine is an N-methyl-D-aspartate (NMDA) receptor antagonist used for levodopa-induced dyskinesias.[83],[84],[105] Guidelines differ regarding the efficacy of amantadine in the management of levodopa-induced dyskinesias. Movement Disorders Society's evidence-based review reported that amantadine was 'efficacious' in the treatment of dyskinesias, whereas the American Association of Neurology (AAN) guidelines concluded that amantadine was 'possibly effective'[83],[126] A recent controlled trial investigated the efficacy and safety of 274 mg of ADS-5102 (amantadine) extended-release capsules (equivalent to 340-mg amantadine hydrochloride) for levodopa-induced dyskinesia. The study reported a significant decrease in levodopa-induced dyskinesia and an improvement in the OFF time.[127]

Patients with PD are troubled by autonomic dysfunction, particularly in the late stage. Pharmacological therapy directed towards the autonomic nervous system includes the use of mineralocorticoid, fludrocortisone, as well as the use of adrenergic agents (such as midodrine and etilefrine), the noradrenaline precursor (that is, droxidopa) to treat orthostatic hypotension; anti-muscarinics (such as oxybutynin, tolterodine or trospium chloride) to treat urinary urgency or incontinence; and, pro-kinetic drugs to improve constipation.[84],[123],[128]

Tyrosine kinase inhibitors for the treatment of PD

Recently, investigations have shown that the levels and activation of Abelson non-receptor tyrosine kinase (c-Abl) were upregulated in the brain tissue of patients with PD. Karuppagounder et al., evaluated the in vivo efficacy of a brain penetrant, c-Abl tyrosine kinase inhibitor, in the acute 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP)-induced model of PD and found that nilotinib prevented dopamine neuronal loss and behavioral deficits following MPTP induced intoxication.[129] Nilotinib reduced c-Abl activation, levels of Parkin substrate and neuronal cell death. Imam et al., tested the efficacy of INNO-406 (a second generation irreversible Abl kinase inhibitor) and found that INNO-406 was capable of preventing the progression of dopaminergic neuronal damage in a toxin-induced C57 mouse model of PD.[130] Researchers have demonstrated that c-Abl inhibitors (nilotinib, imatinib, and to a lesser extent, bafetinib) could prevent the loss of dopamine neurons, improve motor behavior, inhibit phosphorylation of Cdk5, regulate α-synuclein phosphorylation and reduce the levels of Parkin substrate.[131] Brain permeable c-Abl inhibitors can serve as potential therapeutic agents for the treatment of PD and other neurodegenerative disorders.

Surgical treatment

Deep brain stimulation (DBS) of either the subthalamic nucleus (STN) or globus pallidus interna (GPi) is a well-known treatment for patients with motor complications.[132],[133],[134] For treatment of tremors, thalamic DBS is a viable option. Surgical treatment is preferred when motor fluctuations and dyskinesias become disabling despite responsiveness of the motor symptoms to levodopa. The average time before DBS is performed is about 10–13 years after the diagnosis of Parkinson's disease has been established. Findings of the EARLYSTIM trial, a multicenter randomized control trial showed that DBS in the early course of disease (mean disease duration 7.5 years, with motor fluctuations for <3 years) could improve the patient's quality of life and several secondary outcome measures more than the best medical therapy.[135]

DBS is reversible and can be adjusted for disease progression. The presence of dementia, acute psychosis and major depression are the exclusion criteria for DBS.[136] Bilateral DBS of the STN improves the UPDRS II (activities of daily living) and UPDRS III (motor) scores, on an average, by 50–60% compared with the preoperative medical OFF state. The total daily dopaminergic drug dosage is reduced by about 60% following the institution of DBS, and dyskinesias decrease by 60–70%.[137],[138] Subthalamic nucleus (STN) DBS was associated with decreased requirement of levodopa doses.[139] The mortality of DBS is <0.5% and the important adverse events include intracranial bleeding or device-related complications (such as infections and lead misplacements, among others).[140]

Non-pharmacological therapies available for PD include exercise, education, support groups, speech therapy and nutrition. Evidence from literature recommends their usage earlyon in the course of the disease.


 » Conclusion Top


Parkinson's disease is one of the most common neurodegenerative diseases affecting the aging population and is associated with an increased morbidity and mortality. Awareness of the disease manifestations, the treatments, and the progressive long-term course of the disease is necessary for the optimal management of the cases. Tremendous progress has been made in understanding the neuropathology of PD and its progression throughout the nervous system. However, none of these treatments is curative. PD remains a progressive disorder that eventually causes severe disability due to the increasing severity of treatment-resistant motor problems and non-motor symptoms. Modifying factors that lead to the disease progression and in further delaying its disability are the key unmet needs to be addressed by the current and future research efforts.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
 » References Top

1.
Goldman SM, Tanner C. Etiology of Parkinson's's disease. In: Jankovic J, Tolosa E, editors. Parkinson's's disease and movement disorders, 3rd ed. Baltimore, MD: Lippincott-Williams and Wilkins; 1998. p. 133-58.  Back to cited text no. 1
    
2.
Schrag A, Schott JM. Epidemiological, clinical, and genetic characteristics of early-onset Parkinson'sism, Lancet Neurol 2006; 5:355-63.  Back to cited text no. 2
    
3.
Baldereschi M, Di Carlo A, Rocca, WA, Vanni P, Maggi S, Perissinotto E, et al. Parkinson's disease and Parkinsonism in a longitudinal study: Two-fold higher incidence in men. ILSA Working Group. Italian Longitudinal Study on Aging. Neurology 2000;55. 1358-63.  Back to cited text no. 3
    
4.
Van Den Eeden SK, Tanner CM, Bernstein AL, Fross RD, Leimpeter A, et al. Incidence of Parkinson's disease: Variation by age, gender, and race/ethnicity. Am J Epidemiol 2003;157:1015-22.  Back to cited text no. 4
    
5.
Razdan S, Kaul RL, Motta A, Kaul S, Bhatt RK. Prevalence and pattern of major neurological disorders in rural Kashmir (India) in 1986. Neuroepidemiology 1994;13:113-9.  Back to cited text no. 5
    
6.
Gourie Devi M, Gururaj P, Satishchandra P. Bangalore urban and rural neurological survey. Report submitted to the Indian Council of Medical Research;1995.  Back to cited text no. 6
    
7.
Das SK, Sanyal K. Neuroepidemiology of major neurological disorders in rural Bengal. Neurol India 1996;49:47-58.  Back to cited text no. 7
    
8.
Bharucha NE, Bharucha EP, Bharucha AE, Bhise AV, Schoenberg BS. Prevalence of Parkinson's's disease in the Parsi community of Bombay, India. Arch Neurol 1988;45:1321-3.  Back to cited text no. 8
    
9.
Warner TT, Schapira AH. Genetic and environmental factors in the cause of Parkinson's disease. Ann Neurol 2003;53:S16-S23.  Back to cited text no. 9
    
10.
Cookson MR, Xiromerisiou G, Singleton A. How genetics research in Parkinson's disease is enhancing understanding of the common idiopathic forms of the disease. Curr Opin Neurol 2005;18:706-11.  Back to cited text no. 10
    
11.
Marder K, Tang M-X, Mejia-Santana H, Rosado L, Louis ED, Comella C, et al. Predictors of Parkin mutations in early onset parkinson's disease: The CORE-PD Study. Arch Neurol 2010;67:731-8.  Back to cited text no. 11
    
12.
Alcalay R, Caccappolo E, Mejia-Santana H, Tang MX, Rosado L, Ross B, et al. Frequency of known mutations in early onset PD;Implication for genetic counseling: The CORE-PD study. Arch Neurol 2010;67:1116-22.  Back to cited text no. 12
    
13.
Lesage S, Brice A. Parkinson's disease: From monogenic forms to genetic susceptibility factors. Hum Mol Genet 2009;18:R48-59.  Back to cited text no. 13
    
14.
Das SK, Ghosh B, Das G, Biswas A, Ray J. Movement disorders: Indian scenario: A clinico-genetic review. Neurol India 2013;61:457-66.  Back to cited text no. 14
  [Full text]  
15.
Madegowda RH, Kishore A, Anand A. Mutational screening of the Parkin gene among South Indians with early onset Parkinson's disease. J Neurol Neurosurg Psychiatry 2005;76:1588-90.  Back to cited text no. 15
    
16.
Chaudhary S, Behari M, Dihana M, Swaminath PV, Govindappa ST, Jayaram S, Singh S, et al. Parkin mutations in familial and sporadic Parkinson's disease among Indians. Parkinsonism Relat Disord 2006;12:239-45.  Back to cited text no. 16
    
17.
Biswas A, Gupta A, Naiya T, Das G, Neogi R, Datta S, et al. Molecular pathogenesis of Parkinson's disease: Identification of mutations in the Parkin gene in Indian patients. Parkinsonism Relat Disord 2006;12:420-6.  Back to cited text no. 17
    
18.
Vinish M, Prabhakar S, Khullar M, Verma I, Anand A. Genetic screening reveals high frequency of PARK2 mutations and reduced Parkin expression conferring risk for Parkinsonism in North West India. J Neurol Neurosurg Psychiatry 2010;81:166-70.  Back to cited text no. 18
    
19.
Padmaja MV, Jayaraman M, Srinivasan AV, Srisailapathy CR, Ramesh A. PARK2 gene mutations in early onset Parkinson's disease patients of South India. Neurosci Lett 2012;523:145-7.  Back to cited text no. 19
    
20.
Abbas MM, Govindappa ST, Sudhaman S, Thelma BK, Juyal RC, Behari M, et al. Early onset Parkinson's disease due to DJ1 mutations: An Indian study. Parkinsonism Relat Disord 2016;32:20-24.  Back to cited text no. 20
    
21.
Sanyal J, Sarkar B, Banerjee TK, Mukherjee SC, Ray BC, Raghavendra Rao V. Evaluating intra-genetic variants of DJ-1 among Parkinson's disease patients of Eastern India. Neurol Res 2011;33:349-53.  Back to cited text no. 21
    
22.
Sadhukhan T, Biswas A, Das SK, Ray K, Ray J. DJ-1 variants in Indian Parkinson's disease patients. Dis Markers. 2012;33:127-35.  Back to cited text no. 22
    
23.
Gilks WP, Abou-Sleiman PM, Gandhi S, Jain S, Singleton A, Lees AJ, et al. A common LRRK2 mutation in idiopathic Parkinson's disease. Lancet 2005;365:415-6.  Back to cited text no. 23
    
24.
Padmaja MV, Jayaraman M, Srinivasan AV, Srikumari Srisailapathy CR, Ramesh A. The SNCA (A53T, A30P, and E46K) and LRRK2 (G2019S) mutations are rare causes of Parkinson's disease in South Indian patients. Parkinsonism Relat Disord 2012;18:801-2.  Back to cited text no. 24
    
25.
Vijayan B, Gopala S, Kishore A. LRRK2 G2019S mutation does not contribute to Parkinson's disease in South India. Neurol India 2011;59:157-60.  Back to cited text no. 25
[PUBMED]  [Full text]  
26.
Sanyal J, Sarkar B, Ojha S, Banerjee TK, Ray BC, Rao VR. Absence of commonly reported leucine-rich repeat kinase 2 mutations in Eastern Indian Parkinson's disease patients. Genet Test Mol Biomarkers 2010;14:691-4.  Back to cited text no. 26
    
27.
Punia S, Behari M, Govindappa ST, Swaminnath PV, Jayaram S, Goyal V, et al. Absence/rarity of commonly reported LRRK2 mutations in Indian Parkinson's's disease patients. Neurosci Lett 2006;409:83-88.  Back to cited text no. 27
    
28.
Sadhukhan T, Vishal M, Das G, Sharma A, Mukhopadhyay A, Das SK, et al. Evaluation of the role of LRRK2 gene in Parkinson's disease in an East Indian cohort. Dis Markers. 2012;32:355-62.  Back to cited text no. 28
    
29.
Paisan-Ruiz C. LRRK2 gene variation and its contribution to Parkinson's disease. Hum Mutat 2009;30:1153-60.  Back to cited text no. 29
    
30.
Nagar S, Juyal RC, Chaudhary S, Behari M, Gupta M, Rao SN, et al. Mutations in the alpha-synuclein gene in Parkinson's disease among Indians. Acta Neurol Scand 2001;103:120-22.  Back to cited text no. 30
    
31.
Kadakol GS, Kulkarni SS, Wali GM, Gai PB. Molecular analysis of α-synuclein gene in Parkinson's disease in North Karnataka, India. Neurol India 2014;62:149-52.  Back to cited text no. 31
[PUBMED]  [Full text]  
32.
Schapira AH. Mitochondria in the aetiology and pathogenesis of Parkinson's's disease. Lancet Neurol 2008;7:97-109.  Back to cited text no. 32
    
33.
Biswas A, Sadhukhan T, Majumder S, Misra AK, Das SK, Variation Consortium IG, et al. Evaluation of PINK1 variants in Indian Parkinson's's disease patients. Parkinsonism Relat Disord 2010;16:167-71.  Back to cited text no. 33
    
34.
Tamali Halder, Raj J, Sharma V, Das P. Novel P-TEN-induced putative kinase 1 (PINK1) variant in Indian Parkinson's disease patient. Neurosci Lett 2015;605:29-33.  Back to cited text no. 34
    
35.
Sudhaman S, Prasad K, Behari M, Muthane UB, Juyal RC, Thelma BK. Discovery of a frameshift mutation in podocalyxin- like (PODXL) gene, coding for a neural adhesion molecule, as causal for autosomal-recessive juvenile Parkinsonism. J Med Genet 2016;53:450-6.  Back to cited text no. 35
    
36.
Dickson DW, Braak H, Duda JE, Duyckaerts C, Gasser T, Halliday GM, et al. Neuropathological assessment of Parkinson's disease: Refining the diagnostic criteria. Lancet Neurol 2009;8:1150-7.  Back to cited text no. 36
    
37.
Goedert M, Spillantini MG, Del Tredici K, Braak H. 100 years of Lewy pathology. Nat Rev Neurol 2012;9:13-24.  Back to cited text no. 37
    
38.
Postuma RB, Gagnon JF, Montplaisir J. Clinical prediction of Parkinson's disease: Planning for the age of neuroprotection. J Neurol Neurosurg Psychiatry 2009;81:1008-13.  Back to cited text no. 38
    
39.
Halliday, GM, McCann H. The progression of pathology in Parkinson's disease. Ann NY Acad Sci 2010;1184:188-95.  Back to cited text no. 39
    
40.
Dijkstra, AA, Voorn P, Berendse HW, Dijkstra AA, Voorn P, Berendse HW, Groenewegen HJ;Netherlands Brain Bank, Rozemuller AJ, van de Berg WD. Stage-dependent nigral neuronal loss in incidental Lewy body and Parkinson's disease. Mov Disord 2014;29:1244-51. Stage-dependent nigral neuronal loss in incidental Lewy body and Parkinson's disease. Mov Disord 2014;29:1244-51.  Back to cited text no. 40
    
41.
Damier P, Hirsch EC, Agid Y, Graybiel AM. The substantia nigra of the human brain. II. Patterns of loss of dopamine-containing neurons in Parkinson's disease. Brain 1999;122:1437-48.  Back to cited text no. 41
    
42.
Fearnley JM, Lees AJ. Ageing and Parkinson's disease: Substantia nigra regional selectivity. Brain 1991;114:2283-301.  Back to cited text no. 42
    
43.
Alexander GD, DeLong MR, Strick PL. Parallel organization of functionally segregated circuits linking basal ganglia and cortex. Annu Rev Neurosci 1986;9:357-81.  Back to cited text no. 43
    
44.
Alexander G, Crutcher MD, DeLong MR. Basal ganglia-thalamocortical circuits: Parallel substrates for motor, oculomotor, “prefrontal” and “limbic” functions. Prog Brain Res 1990;85:119-46.  Back to cited text no. 44
    
45.
Dirkx MF, den Ouden H, Aarts E, Timmer M, Bloem BR, Toni I, et al. The cerebral network of Parkinson's tremor: An effective connectivity fMRI Study. J Neurosci 2016;36:5362-72.  Back to cited text no. 45
    
46.
Windels F, Thevathasan W, Silburn P, Sah P. Where and what is the PPN and what is its role in locomotion? Brain 2015;138:1133-4.  Back to cited text no. 46
    
47.
Mulak A, Bonaz B. Brain-gut-microbiota axis in Parkinson's disease. World J Gastroenterol 2015;21:10609-20.  Back to cited text no. 47
    
48.
Sampson TR, Debelius JW, Thron T, Janssen S, Shastri GG, Khan ZE, et al. Gut microbiota regulate motor deficits and neuroinflammation in a model of Parkinson's disease. Cell. 2016;167:1469-80.  Back to cited text no. 48
    
49.
Scheperjans F, Aho V, Pereira PA, Koskinen K, Paulin L, Pekkonen E, et al. Gut microbiota are related to Parkinson's disease and clinical phenotype. Mov Disord 2015;30:350-8.  Back to cited text no. 49
    
50.
Keshavarzian A, Green SJ, Engen PA, Voigt RM, Naqib A, Forsyth CB, et al. Colonic bacterial composition in Parkinson's disease. Mov Disord 2015;30:1351-60.  Back to cited text no. 50
    
51.
Unger MM, Spiegel J, Dillmann KU, Grundmann D, Philippeit H, Bürmann J, et al. Short chain fatty acids and gut microbiota differ between patients with Parkinson's disease and age-matched controls. Parkinsonism Relat Disord 2016;32:66-72.  Back to cited text no. 51
    
52.
Hasegawa S, Goto S, Tsuji H, Okuno T, Asahara T, Nomoto K, et al. Intestinal dysbiosis and lowered serum lipopolysaccharide-binding protein in Parkinson's's disease. PLoS ONE 2015;10:e0142164. Available from: https://doi.org/10.1371/journal.pone. 0142164. [Last accessed on 2018 Jan 22].  Back to cited text no. 52
    
53.
Hill-Burns EM, Debelius JW, Morton JT, Wissemann WT, Lewis MR, Wallen ZD, et al. Parkinson's disease and Parkinson's disease medications have distinct signatures of the gut microbiome. Mov Disord 2017;32:739-49.  Back to cited text no. 53
    
54.
Hughes AJ, Daniel SE, Kilford L, Lees AJ. Accuracy of clinical diagnosis of idiopathic Parkinson's disease. A clinico-pathological study of 100 cases. J Neurol Neurosurg Psychiatry 1992;55:181-4.  Back to cited text no. 54
    
55.
Chaudhuri KR, Schapira AH. Non-motor symptoms of Parkinson's's disease: Dopaminergic pathophysiology and treatment. Lancet Neurol 2009;8:464-74.  Back to cited text no. 55
    
56.
Hely MA, Reid WG, Adena MA, Halliday GM, Morris JG. The Sydney multicenter study of Parkinson's's disease: The inevitability of dementia at 20 years. Mov Disord 2008;23:837-44.  Back to cited text no. 56
    
57.
Jankovic J, McDermott M, Carter J, Gauthier S, Goetz C, Golbe L, et al. Variable expression of Parkinson's disease: A base-line analysis of the DATATOP cohort. The Parkinson's Study Group. Neurology 1990;40, 1529-34.  Back to cited text no. 57
    
58.
Lim SY, Lang AE. The nonmotor symptoms of Parkinson's disease-An overview. Mov Disord 2010;25(Suppl 1):S123-S130.  Back to cited text no. 58
    
59.
Noyce AJ, Bestwick JP, Silveira-Moriyama L, Hawkes CH, Giovannoni G, Lees AJ, et al. Meta-analysis of early nonmotor features and risk factors for Parkinson's disease. Ann Neurol 2012;72:893-901.  Back to cited text no. 59
    
60.
Salat D, Noyce AJ, Schrag A, Tolosa E. Challenges of modifying disease progression in pre-diagnostic Parkinson's disease. Lancet Neurol 2016;15:637-48.  Back to cited text no. 60
    
61.
Postuma RB, Aarsland D, Barone P, Bum DJ, Hawkes CH, Oertel CH, et al. Identifying prodromal Parkinson's disease: Pre-motor disorders in Parkinson's disease. Mov Disord 2012;27:617-26.  Back to cited text no. 61
    
62.
Lohle M, Storch A, Reichmann H. Beyond tremor and rigidity: Non-motor features of Parkinson's Disease. J Neural Transm (Vienna) 2009;116:1483-92.  Back to cited text no. 62
    
63.
Aarsland D, Beyer MK, Kurz MW. Dementia in Parkinson's disease. Curr Op Neurol 2008;21:676-82.  Back to cited text no. 63
    
64.
Xiao Q, Chen S, Le W. Hyposmia: A possible biomarker of Parkinson's's disease. Neurosci Bull 2014;30:134-40.  Back to cited text no. 64
    
65.
Rizzo G, Copetti M, Arcuti S, Martino D, Fontana A, Logroscino G. Accuracy of clinical diagnosis of Parkinson's disease: A systematic review and meta- analysis. Neurology 2016 86:566-76.  Back to cited text no. 65
    
66.
Stoessl AJ, Lehericy S, Strafella AP. Imaging insights into basal ganglia function, Parkinson's disease, and dystonia. Lancet 2014;384:532-44.  Back to cited text no. 66
    
67.
Politis M. Neuroimaging in Parkinson's disease: From research setting to clinical practice. Nat Rev Neurol 2014;10:708-22.  Back to cited text no. 67
    
68.
Ibrahim N, Kusmirek J, Struck AF, Floberg JM, Perlman SB, Gallagher C, et al. The sensitivity and specificity of F-DOPA PET in a movement disorder clinic. Am J Nucl Med Mol Imaging 2016;6:102-9.  Back to cited text no. 68
    
69.
Ishikawa T, Dhawan V, Kazumata K, Chaly T, Mandel F, Neumeyer J, et al. Comparative nigrostriatal dopaminergic imaging with iodine-123-beta CIT- FP/SPECT and fluorine-18-FDOPA/PET. J Nucl Med 1996;37:1760-5.  Back to cited text no. 69
    
70.
Eshuis SA, Maguire RP, Leenders KL, Jonkman S, Jager PL. Comparison of FP-CIT SPECT with F-DOPA PET in patients with de novo and advanced Parkinson's's disease. Eur J Nucl Med Mol Imaging 2006;33:200-9.  Back to cited text no. 70
    
71.
Eshuis SA, Jager PL, Maguire RP, Jonkman S, Dierckx RA, Leenders KL, et al. Direct comparison of FP-CIT SPECT and F-DOPA PET in patients with Parkinson's disease and healthy controls. Eur J Nucl Med Mol Imaging 2009;36:454-62.  Back to cited text no. 71
    
72.
Lehéricy S, Sharman MA, Santos CLD, Paquin R, Gallea C. Magnetic resonance imaging of the substantia nigra in Parkinson's's disease. Mov Disord 2012;27:822-30.  Back to cited text no. 72
    
73.
Mahlknecht P, Hotter A, Hussl A, Esterhammer R, Schocke M, Seppi K. Significance of MRI in diagnosis and differential diagnosis of Parkinson's disease. Neurodegener Dis 2010;7:300-18.  Back to cited text no. 73
    
74.
Treglia G, Cason E, Stefanelli A, Cocciolillo F, Di Giuda D, Fagioli G, et al. MIBG scintigraphy in differential diagnosis of Parkinsonism: A meta-analysis. Clin Auton Res 2012;22, 43-55.  Back to cited text no. 74
    
75.
Chen-Plotkin AS. Unbiased approaches to biomarker discovery in neurodegenerative diseases. Neuron 2014;84:594-607.  Back to cited text no. 75
    
76.
Swanson CR, Berlyand Y, Xie SX, Alcalay RN, Chahine LM, Chen-Plotkin AS. Plasma ApoA1 associates with age at onset and motor severity in early Parkinson's disease patients. Mov Disord 2015;30:1648-56.  Back to cited text no. 76
    
77.
Schapira AHV. Recent developments in biomarkers in Parkinson's disease. Curr Opin Neurol 2013;26:395-400.  Back to cited text no. 77
    
78.
Miyasaki JM, Martin W, Suchowersky O, Weiner WJ, Lang AE. Practice parameter: Initiation of treatment for Parkinson's disease: An evidence-based review: Report of the quality standards subcommittee of the American Academy of Neurology. Neurology 2002;58:11-17.  Back to cited text no. 78
    
79.
Antonini A, Bernardi L, Calandrella D, Mancini F, Plebani M. Rotigotine transdermal patch in the management of Parkinson's disease (PD) and its night-time use for PD-related sleep disorders. Funct Neurol 2010;25:21-5.  Back to cited text no. 79
    
80.
Fernandez HH, Vanagunas A, Odin P, Espay AJ, Hauser RA, Standaert DG, et al. Levodopa-carbidopa intestinal gel in advanced Parkinson's disease open-label study: Interim results. Parkinsonism Relat Disord 2013;19:339-45.  Back to cited text no. 80
    
81.
Olanow CW, Kieburtz K, Odin P, Espay AJ, Standaert DG, Fernandez HH, et al. Continuous intrajejunal infusion of levodopa-carbidopa intestinal gel for patients with advanced Parkinson's disease: A randomised, controlled, double-blind, double-dummy study. Lancet Neurol 2014;13:141-49.  Back to cited text no. 81
    
82.
Poewe W., Antonini A. Novel formulations and modes of delivery of levodopa. Mov Disord 2015;30:114-20.  Back to cited text no. 82
    
83.
Fox SH, Katzenschlager R, Lim S-Y, Ravina B, Seppi K, Coelho M, et al. The Movement Disorder Society evidence-based medicine review update: Treatments for the motor symptoms of Parkinson's disease. Mov Disord 2011;26:S2-41.  Back to cited text no. 83
    
84.
Connolly B, Lang AE. Pharmacological treatment of Parkinson's disease: A review. JAMA 2014;311:1670-83.  Back to cited text no. 84
    
85.
LeWitt PA, Fahn S. Levodopa therapy for Parkinson's disease: A look backward and forward. Neurology 2016;86:S3-S12.  Back to cited text no. 85
    
86.
Olanow CW, Obeso JA, Stocchi F. Continuous dopamine-receptor treatment of Parkinson's disease: Scientific rationale and clinical implications. Lancet Neurol 2006;5:677-87.  Back to cited text no. 86
    
87.
Cenci MA. Presynaptic mechanisms of l-DOPA- induced dyskinesia: The findings, the debate, and the therapeutic implications. Front Neurol 2014;5:242.  Back to cited text no. 87
    
88.
Hauser RA, Ellenbogen AL, Metman LV, Hsu A, O'Connell MJ, Modi NB, et al. Crossover comparison of IPX066 and a standard levodopa formulation in advanced Parkinson's disease. Mov Disord 2011;26:2246-52.  Back to cited text no. 88
    
89.
Hauser RA, Hsu A, Kell S, Espay AJ, Sethi K, Stacy M, et al. Extended-release carbidopa-levodopa (IPX066) compared with immediate-release carbidopa-levodopa in patients with Parkinson's disease and motor fluctuations: A phase 3 randomised, double-blind trial. Lancet Neurol 2013;12:346- 56.  Back to cited text no. 89
    
90.
Pahwa R, Lyons KE, Hauser RA, Fahn S, Jankovic J, Porcher E, et al. Randomized trial of IPX066, carbidopa/levodopa extended release, in early Parkinson's disease. Parkinsonism Relat Disord 2014;20:142-8.  Back to cited text no. 90
    
91.
Stocchi F, Hsu A, Khanna S, Ellenbogen A, Mahler A, Liang G, et al. Comparison of IPX066 with carbidopa-levodopa plus entacapone in advanced PD patients. Parkinsonism Relat Disord 2014;20:1335-40.  Back to cited text no. 91
    
92.
Waters CH, Nausieda P, Dzyak L, Spiegel J, Rudzinska M, Silver DE, et al. Long-term treatment with extended-release carbidopa-levodopa (IPX066) in early and advanced Parkinson's disease: A 9-month open-label extension trial. CNS Drugs 2015;29:341-50.  Back to cited text no. 92
    
93.
Dhall R, Kreitzman DL. Advances in levodopa therapy for Parkinson's disease: Review of RYTARY (carbidopa and levodopa) clinical efficacy and safety. Neurology 2016;86:S13-24.  Back to cited text no. 93
    
94.
Fernandez HH, Standaert DG, Hauser RA, Lang AE, Fung VS, Klostermann F, et al. Levodopa-carbidopa intestinal gel in advanced Parkinson's disease: Final 12-month, open-label results. Mov Disord 2015;30:500-9.  Back to cited text no. 94
    
95.
LeWitt PA, Friedman H, Giladi N. Accordion pill carbidopa/levodopa for improved treatment of advanced Parkinson's disease symptoms. Mov Disord 2012;27(Suppl 1):S408.  Back to cited text no. 95
    
96.
LeWitt P, Friedman H, Giladi N. Sustained-release carbidopa-levodopa (accordian pill) in patients with advanced Parkinson's disease: Pharmacokinetic and clinical experience. Mov Disord 2013;28(Suppl. 1):S499.  Back to cited text no. 96
    
97.
LeWitt PA, Giladi N, Gurevich T. Accordion pill carbidopa/levodopa (AP-CD/LD) for treatment of advanced Parkinson's disease (PD). Mov Disord. 2014;29(Suppl. 1):S668.  Back to cited text no. 97
    
98.
Caraco Y, Oren S, LeWitt P. Constant therapeutic levodopa (LD) plasma concentrations maintained by continuous subcutaneous (SC) administration of ND-0612, a novel formulation of LD/carbidopa (CD). Mov Disord 2013;28(Suppl. 1):S452.  Back to cited text no. 98
    
99.
Giladi N, Caraco Y, Gurevich T, Djaldetti R. Pharmacokinetics and safety of ND0612L (levodopa/carbidopa for subcutaneous infusion): Results from a phase II study in moderate to severe Parkinson's disease. Neurology 2015;84(Suppl. P1):187.  Back to cited text no. 99
    
100.
Muller T, Kuoppamaki M, Vahteristio M, Aho V. Novel levodopa product ODM-101 vs levodopa/carbidopa/entacapone in Parkinson's disease with response fluctuations. Mov Disord 2013;28:S146.  Back to cited text no. 100
    
101.
Lewitt PA, Hauser RA, Grosset DG, Stocchi F, Saint-Hilaire MH, Ellenbogen A, et al. A randomized trial of inhaled levodopa (CVT-301) for motor fluctuations in Parkinson's disease. Mov Disord 2016;31:1356-65.  Back to cited text no. 101
    
102.
Luinstra M, Grasmeijer F, Hagedoorn P, Moes JR, Frijlink HW, de Boer AH. A levodopa dry powder inhaler for the treatment of Parkinson's disease patients in off periods. Eur J Pharm and Biopharm 2015;97:22-29.  Back to cited text no. 102
    
103.
PD MED Collaborative Group. Long-term effectiveness of dopamine agonists and monoamine oxidase B inhibitors compared with levodopa as initial treatment for Parkinson's disease (PD MED): A large, open-label, pragmatic randomised trial. Lancet 2014;384:1196-205.  Back to cited text no. 103
    
104.
Lang AE, Marras C. Initiating dopaminergic treatment in Parkinson's disease. Lancet 2014;384:1164-1166.  Back to cited text no. 104
    
105.
Jankovic J, Poewe W. Therapies in Parkinson's disease. Curr Opin. Neurol 2012;25:433-47.  Back to cited text no. 105
    
106.
Frankel JP, Lees AJ, Kempster PA, Stern GM. Subcutaneous apomorphine in the treatment of Parkinson's disease. J Neurol Neurosurg Psychiatry 1990;53:96-101.  Back to cited text no. 106
    
107.
Katzenschlager R, Hughes A, Evans A, Manson AJ, Hoffman M, Swinn L et al. Continuous subcutaneous apomorphine therapy improves dyskinesias in Parkinson's disease: A prospective study using single-dose challenges. Mov Disord 2005;20:151-7.  Back to cited text no. 107
    
108.
Birkmayer W, Riederer P, Ambrozi L, Youdim MB. Implications of combined treatment with 'Madopar' and L-deprenil in Parkinson's disease. A long-term study. Lancet 1977;1:439-43.  Back to cited text no. 108
    
109.
Palhagen S, Heinonen E. Use of selegiline as monotherapy and in combination with levodopa in the management of Parkinson's disease: Perspectives from the MONOCOMB study. Progress in Neurotherapeutics and Neuropsychopharmacology. 2008;3:49-71.  Back to cited text no. 109
    
110.
Mizuno Y, Hattori N, Kondo T, Nemoto M, Origasa H, Takahashi R, et al. A randomized double-blind placebo-controlled phase iii trial of selegiline monotherapy for early Parkinson's disease. Clin Neuropharmacol 2017;40:201-7.  Back to cited text no. 110
    
111.
Cereda E, Cilia R, Canesi M, Tesei S, Mariani CB, Zecchinelli AL, et al. Efficacy of rasagiline and selegiline in Parkinson's disease: A head-to-head 3-year retrospective case-control study. J Neurol 2017;264:1254-63.  Back to cited text no. 111
    
112.
deSouza RM, Schapira A. Safinamide for the treatment of Parkinson's disease. Expert Opin Pharmaco 2017;18:937-43.  Back to cited text no. 112
    
113.
Schapira AH, Fox SH, Hauser RA, Jankovic J, Jost WH, Kenney C, et al. Assessment of safety and efficacy of safinamide as a levodopa adjunct in patients with Parkinson's disease and motor fluctuations: A randomized clinical trial. JAMA Neurol 2017;74:216-24.  Back to cited text no. 113
    
114.
Muller T. Catechol-O-methyltransferase inhibitors in Parkinson's disease. Drugs 2015;75:157-74.  Back to cited text no. 114
    
115.
Bonifácio MJ, Palma PN, Almeida L, Soares-da-Silva P. Catechol-O-methyltransferase and its inhibitors in Parkinson's disease. CNS Drug Reviews 2007;13:352-79.  Back to cited text no. 115
    
116.
Learmonth DA, Vieira-Coelho MA, Benes J, Alves PC, Borges N, Freitas AP, et al. Synthesis of 1-(3,4-dihydroxy-5-nitrophenyl)-2-phenyl-ethanone and derivatives as potent and long-acting peripheral inhibitors of catechol-O-methyltransferase. J Med Chem 2002;45:685-95.  Back to cited text no. 116
    
117.
Rodrigues BF, Ferreira JJ. Opicapone for the treatment of Parkinson's disease. Expert Opin Pharmacother 2017;18:445-53.  Back to cited text no. 117
    
118.
Kalia LV, Brotchie JM, Fox SH. Novel nondopaminergic targets for motor features of Parkinson's's disease: Review of recent trials. Mov Disord 2013;28:131-44.  Back to cited text no. 118
    
119.
Yarnall A, Rochester L, Burn DJ. The interplay of cholinergic function, attention, and falls in Parkinson's's disease. Mov Disord 2011;26:2496-503.  Back to cited text no. 119
    
120.
Chung KA, Lobb BM, Nutt JG, Horak FB. Effects of a central cholinesterase inhibitor on reducing falls in Parkinson's disease. Neurology 2010;75:1263-9.  Back to cited text no. 120
    
121.
Emre M, Aarsland D, Albanese A, Byrne EJ, Deuschl G, De Deyn PP, et al. Rivastigmine for dementia associated with Parkinson's disease. N Engl J Med 2004;351:2509-18.  Back to cited text no. 121
    
122.
Henderson EJ, Lord SR, Close JC, Lawrence AD, Whone A, Ben-Shlomo T. The respond trial—rivastigmine to stabilise gait in Parkinson's's disease a phase II, randomised, double blind, placebo controlled trial to evaluate the effect of rivastigmine on gait in patients with Parkinson's disease who have fallen. BMC Neurol 2013;13:188.  Back to cited text no. 122
    
123.
Seppi, K, Weintraub D, Coelho M, Perez-Lloret S, Fox SH, Katzenschlager R, et al. The Movement Disorder Society evidence-based medicine review update: Treatments for the non-motor symptoms of Parkinson's disease. Mov Disord 2011;26:S42-S80.  Back to cited text no. 123
    
124.
Connolly B, Fox SH. Treatment of cognitive, psychiatric, and affective disorders associated with Parkinson's disease. Neurotherapeutics 2014;11:78-91.  Back to cited text no. 124
    
125.
Cummings J, Isaacson S, Mills R, William H, Chi-Burris K, Corbett A, et al. Pimavanserin for patients with Parkinson's disease psychosis: A randomised, placebo-controlled phase 3 trial. Lancet 2014;383:533-40.  Back to cited text no. 125
    
126.
Pahwa R, Factor SA, Lyons KE, Ondo WG, Gronseth G, Bronte-Stewart H, et al. Practice parameter: Treatment of Parkinson's disease with motor fluctuations and dyskinesia (an evidence-based review): Report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology 2006;66:983-95.  Back to cited text no. 126
    
127.
Oertel W, Eggert K, Pahwa R, Tanner CM, Hauser RA, Pahwa R, et al. Randomized, placebo-controlled trial of ADS-5102 (amantadine) extended-release capsules for levodopa-induced dyskinesia in Parkinson's disease (EASE LID 3). Move Disord 2017;32:1701-9.  Back to cited text no. 127
    
128.
Perez-Lloret S, Rey MV, Pavy-Le Traon A, Rascol O. Emerging drugs for autonomic dysfunction in Parkinson's disease. Expert Opin Emerg Drugs 2013;18:39-53.  Back to cited text no. 128
    
129.
Karuppagounder SS, Brahmachari S, Lee Y, Dawson VL, Dawson TM, Ko HS. The c-Abl inhibitor, nilotinib, protects dopaminergic neurons in a preclinical animal model of Parkinson's disease. Sci Rep 2014;4:4874.  Back to cited text no. 129
    
130.
Imam SZ, Trickler W, Kimura S, Binienda ZK, Paule MG, Slikker W Jr, et al. Neuroprotective efficacy of a new brain-penetrating C-Abl inhibitor in a murine Parkinson's disease model. PLoS one 2013;8:e65129.  Back to cited text no. 130
    
131.
Zhou, ZH, Wu YF, Wang X, Hahn YZ. The c-Abl inhibitor in Parkinson's disease. Neurol Sci 2017;38:547-52.  Back to cited text no. 131
    
132.
Kalia SK, Sankar T, Lozano AM. Deep brain stimulation for Parkinson's disease and other movement disorders. Curr Opin Neurol 2013;26:374-80.  Back to cited text no. 132
    
133.
Schuepbach WMM, Rau J, Knudsen K, Krack VP, Timmermann L, Halbig TD, et al. Neurostimulation for Parkinson's disease with early motor complications. N Engl J Med 2013;368:610-22.  Back to cited text no. 133
    
134.
Manjunath M, Yadav R, Dwarakanath S, Jhunjhunwala K, Jafar A, Surathi P, Lenka A, Stezin A, Sampath S, Pal PK. Experience of pallidal deep brain stimulation in dystonia at a tertiary care centre in India: An initial experience. Neurol India 2017;65:1322-9  Back to cited text no. 134
    
135.
Pandey S. When to do deep brain stimulation surgery in Parkinson disease? Early or late?. Neurol India 2016;64:8-9.  Back to cited text no. 135
    
136.
Bronstein JM, Tagliati M, Alterman RL, Lozano AM, Volkmann J, Stefani A, et al. Deep brain stimulation for Parkinson's disease: An expert consensus and review of key issues. Arch Neurol 2011;68:165-71.  Back to cited text no. 136
    
137.
Deuschl G, Agid Y. Subthalamic neurostimulation for Parkinson's disease with early fluctuations: Balancing the risks and benefits. Lancet Neurol 2013;12:1025-34.  Back to cited text no. 137
    
138.
Pandey S, Sarma N. Deep brain stimulation: Current status. Neurol India 2015;63:9-18.  Back to cited text no. 138
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139.
Levine CB, Fahrbach KR, Siderowf AD, Estok RP, Ludensky VM, Ross SD, et al. Diagnosis and treatment of Parkinson's disease: A systematic review of the literature: Summary. 2003 May. In: AHRQ Evidence Report Summaries. Rockville (MD): Agency for Healthcare Research and Quality (US);1998-2005. 57. Available from: https://www.ncbi.nlm.nih.gov/books/NBK11895. [Last accessed on 2018 Jan 22].  Back to cited text no. 139
    
140.
Voges J, Hilker R, Bötzel K, Kiening KL, Kloss M, Kupsch A, et al. Thirty days complication rate following surgery performed for deep-brain-stimulation. Mov Disord 2007;22: 1486-9.  Back to cited text no. 140
    




 

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