Parkinson’s Disease

Introduction

Parkinson’s disease is a slowly progressive and degenerative movement disorder that is characterized by asymmetric resting tremor, rigidity, bradykinesia, gait instability, and postural instability. Of these characteristics, the most common initial motor symptom is a resting tremor in an upper extremity. The tremor is generally asymmetric. The major findings in Parkinson’s disease include the loss of dopaminergic neurons in the substantia nigra pars compacta and the presence of Lewy bodies; even so, there is no definitive test that can confirm a diagnosis of Parkinson’s disease during a person's life. As such, a diagnosis of Parkinson’s disease is a clinical one; it is only considered definitive after an autopsy.

Parkinson’s Disease: A Heterogeneous Disorder

What is becoming more evident is that Parkinson’s disease (PD) is a heterogeneous disorder. This has led to proposals to divide PD into two sub- types: 1) Tremor-dependent PD and 2) Postural Instability and Gait Difficulty PD. Parkinson’s disease is seen more frequently in men. There appears to be forms of PD with a genetic basis. Parkinson’s disease is also associated with several comorbidities such as testosterone deficiency or lower bone density.

The Movement Disorder Society (MDS) defines Parkinson’s disease as a combined syndrome consisting of “A motor clinical syndrome, with levodopa- responsive parkinsonism, typical clinical characteristics, and an absence of markers suggestive of other disease” and “Pathologic confirmation of α- synuclein (α-Syn) deposition and dopamine neuronal loss in the substantia

1 ce4less.com ce4less.com ce4less.com ce4less.com ce4less.com ce4less.com nigra pars compacta (SNpc). Only at this point is the diagnosis termed “definite.” If typical synuclein pathology is not found, the clinical diagnosis is considered incorrect. Likewise, the pathology is “incidental” in the absence of clinical symptoms or attributed to another disease if parkinsonism did not dominate the clinical picture...”1

Parkinson’s disease is slightly more predominant in men, though this increases with age. In individuals aged 50 - 59, the prevalence per 100,000 individuals is 41 in females and 134 in males.1 A recent systematic review and meta-analysis was published synthesizing 47 studies from 1985 to 2010. The studies were geographically diverse, covering North and South America, Asia, Europe and Africa. The prevalence of PD per 100,000 people in general was shown to increase with age: • 41 (95% CI 20-81) for individuals aged 40-49 years • 107 (95% CI 54-211) for individuals aged 50-59 years • 173 (95% CI 88-340) for individuals aged 55-64 years • 428 (95% CI 235-780) for individuals aged 60-69 years • 425 (95% CI 193-939) for individuals aged 65-74 years • 1,087 (95% CI 627-1,883) for individuals aged 70-79 years • 1,903 (95% CI 1,132-3,198) for individuals aged more than 80 years

There was some geographic difference noted in the review. For individuals between the ages of 70 and 79, prevalence in Asian patients was less than half of those individuals from Europe, North America and Australia and less than a third of those from South America.2 Gender prevalence of PD (males versus females per 100,000) was shown to vary with age: • 36 vs. 45 for individuals aged 40-49 years • 134 vs. 41 for individuals aged 50-59 years • 233 vs. 150 for individuals aged 55-64 years

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• 389 vs. 392 for individuals aged 60-69 years • 706 vs. 610 for individuals aged 65-74 years • 932 vs. 813 for individuals aged 70-79 years • 2,101 vs. 1,517 for individuals aged more than 80 years

Genetics

There appears to be forms of PD with a genetic predisposition, with both autosomal dominant and autosomal recessive inheritance. Overall, approximately 15% of cases have a family history of PD. The genes that have been identified to date as being linked to PD include LRRK2, PARK7, PINK1, PRKN, and SNCA genes.1 In mutations of either the LRRK2 or the SNCA gene, inheritance is in an autosomal dominant pattern while in mutations of the PARK7, PINK1 or the PRKN gene, inheritance is in an autosomal recessive pattern.

The LRRK2 gene (DRDN), found on chromosome 12, codes for dardarin, a protein Oxidative stress results from the reaction of reactive with both kinase and GRPase activity. Over radicals such as reactive oxygen or nitrogen species 100 different, single amino acid mutations (ROS/RNS) on DNA and cellular proteins that results are known in families with late-onset PD. In in cell damage or death.

Basque populations, the most common mutations replace arginine with glycine at position 1441 (Arg1441Gly). In North African Arabs and those of Ashkenazi Jewish background, the most common mutation replaces glycine with serine at position 2019 (Gly2019Ser). In Chinese and Japanese populations, the most common mutation replaces glycine with arginine at position 2385 (Gly2385Arg).1

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The PARK7 gene (Parkinson7, DJ-1), found on chromosome 1, codes for the DJ-1 protein. The precise function of the DJ-1 is not known, though it appears to protect against oxidative stress. DJ-1 could also function as a molecular chaperone. Chaperone molecules play a part in the folding of newly produced proteins and the delivery of damaged proteins to proteasomes for proteolysis. Over 25 different mutations located on the PARK7 gene have been associated with PD. The mutations in PARK7 have been associated with the early-onset form of PD. It is unknown if the altered chaperone function of the DJ-1 protein resulting from these mutations is causally related to PD or if another unknown function is more critical to the etiology of PD.1

The PINK1 gene (PTEN-Induced Putative Kinase 1, PARK6), found on chromosome 1, codes for the PTEN-induced putative kinase1 protein. PTEN- 1 is found at highest levels in the heart and the testes and is found within mitochondria. It appears to protect the mitochondria during periods of high energy demands. Over 70 different mutations inPTEN-1 have been seen in patients with PD, often removing the kinase functionality of the protein.1

The PRKN gene (parkin RBR E3 ubiquitin protein ligase, AR-JP, PARK2), found on chromosome 6, codes for a protein, parkin, which tags damaged, nonfunctional or excess proteins with ubiquitin. Ubiquitin acts as a flag for movement into proteasomes and eventual proteolysis. Parkin may also be involved in the destruction of damaged or otherwise non-functional mitochondria. In addition, parkin may function as a tumor suppressor protein and regulate the production and release of neurotransmitters.1 Over 200 mutations of the PRKN gene have been associated with PD, more commonly with early-onset PD but also with late-onset PD.1

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The GBA gene (glucocerebrosidase) encodes for a lysosomal enzyme associated with PD and may be involved in the clearance of α-synuclein aggregates which play a role in the formation of Lewy bodies. GBA deficiency is also associated with Gaucher’s disease. Individuals with a GBA-associated parkinsonism tend to show symptoms at a younger age and a higher frequency of cognitive changes.1 In Ashkenazi Jews with PD, 15% carried a GBA mutation in one study. In another study, 31.3% of PD patients of Ashkenazi background carried a GBA mutation.2

Most cases of PD, however, appear to be the result of a complex interaction of genetic, medical history and environmental factors, though a recent large- scale meta-analysis of genome-wide association data has identified an additional 28 loci associated with PD.2

Risk Factors

There are a number of potential risk factors that have been associated with PD. Increasing age remains the most significant risk factor but the disorder is also consistently associated with pesticide exposure, a history of head trauma that includes an episode of unconsciousness, family history of PD, poliomyelitis, or melanoma, elevated total serum cholesterol levels, higher intake of dairy products (in men), higher levels of serum IL-6, olfactory impairment and trichloroethylene exposure.2-5 Parkinson’s disease is also associated with a family history of melanoma (1st degree relatives). No association of PD has been seen with a family history of colorectal, lung, prostate or breast cancer. In fact, a recent large national record-linkage study found that PD is associated with a decreased risk of cancer with an increased risk of melanoma and breast cancer.2

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Conversely, it is less likely that risk factors for PD include mild traumatic brain injury (TBI), smoking or tobacco use, caffeine consumption, alcohol consumption, or a diet high in unsaturated fats. In fact, many of these are inversely related to the risk of PD.14-16

Parkinson’s disease is also associated with several comorbidities including testosterone deficiency, elevated total cholesterol, lower bone density, increased risk of falls, Vitamin D deficiency and anxiety disorders.2 In one prospective cohort study looking at 24,773 Finnish men and 26,153 Finnish women, with 321 of the men and 304 of the women developing PD, total cholesterol greater than 270mg/dL had a hazard ratio of 1.86. However, elevated cholesterol levels after the age of 55 did not appear to be correlated with PD.2 On the other hand, a more recent prospective study examining the effects of statin use on the risk of PD, found that statins are not protective against PD and that elevated total cholesterol may be associated with a lower risk of Parkinson’s.2 An umbrella review of meta- analyses regarding environmental risk factors of PD concluded that many "environmental factors have substantial evidence of association with Parkinson's disease, but several, perhaps most, of them may reflect reverse causation, residual confounding, information bias, sponsor conflicts or other caveats.”2

Other risks for PD include Hepatitis C (but not Hepatitis B or Hepatitis C with co-infection with Hepatitis B) infection.2 Parkinson’s disease is also associated with gastrointestinal dysfunction.2 The entire length of the GI system may be affected. The complications include dental problems, drooling, difficulty swallowing, delays in gastric emptying times (in addition to the levodopa-induced decrease in emptying times), constipation, increased incidence of small intestinal bacterial overgrowth (SIBO), and

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Heliobacter pylori infections. These dysfunctions can result in malnutrition and malabsorption of medications. The dysregulation often precedes motor symptoms and may significantly contribute to the pathogenesis of PD.2 Factors that have been suggested or implicated as risk factors for PD but have not been shown to be significant include mild traumatic brain injury (TMI), statin use, or residence near power lines (220-380 kV).2

Pathogenesis Of Parkinson’s Disease

The major findings in Parkinson’s disease include the loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc) and the presence of Lewy bodies. However, currently PD is still a clinical diagnosis based on symptomology and responsiveness to dopaminergic therapy.2

Mitochondrial Dysfunction

Mitochondria are thought to be the key targets in PD, with impaired and damaged mitochondria contributing to the death of dopaminergic neurons. The critical role of mitochondria may explain the association of environmental toxins; toxins such as 1-methyl-4-phenyl-1,2,3,6 tetrahydropyridine (MPTP) are metabolized via monoamine oxidase B (MAOB) into 1-methyl-4-phenyl-pyridium (MPP+). MPP+ is concentrated within the mitochondria via the dopamine transporter, eventually leading to inhibition of mitochondrial complex I, opening of the mitochondrial permeability transition pore (mPTP) and depolarization of the mitochondrial membrane. With the membrane depolarized and mPTP open, cytochrome c and apoptosis-inducing factor (AIF) are affected, ultimately leading to cell death.2,3

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Mitochondrial Complex I (NADH Coenzyme Q oxidoreductase, NADH: ubiquinone oxidoreductase, NADH dehydrogenase) is one of the mitochondrial redox enzymes and functions early in the electron transport chain. Inhibition of mitochondrial complex I has been noted in patients with PD. Additionally, inhibitors of mitochondrial complex I such as 1-methyl-4- phenyl-1,2,3,4-tetrahydropyridine (MPTP) and the pesticide rotenone have been shown to produce parkinsonian syndromes.2,3

Oxidative stress, the over-production or the inefficient removal of free radicals such as reactive oxygen species (ROS) and reactive nitrogen species (RNS), has also been implicated in the pathogenesis of PD. Mitochondrial complex I is a major source of peroxide production and can contribute to the process. In addition, mutations of DJ-1 (PARK7) can result in increases in ROS.2

Proteasome Dysfunction

The ubiquitin-proteasome pathway, along with the autophagy-lysosome pathway are critically important in cellular homeostasis. The proteasome is a highly-organized protease complex that carries out systematic and regulated proteolysis of tagged intracellular proteins. Polymerized ubiquitin serves to tag senescent, misfolded and damaged proteins for proteolysis. Proteasomal activity is involved in regulating the cell cycle, cellular differentiation and regulation of the immune system.

The DJ1 (PARK7) protein is believed to be a regulator of proteasome function and protects cells from oxidative stress. Mutations of the DJ1 gene which result in either the dysfunction or lack of function of the DJ1 protein may disturb proteasomal function and result in the autosomal recessive, familial and early onset form of PD that has been recognized for many

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Motor Circuits

The basal ganglia motor circuit modifies cortical output. The cerebral cortex sends signals to the basal ganglia-thalamocortical motor circuit. The signals are modified through the globus pallidus and substantia nigra pars reticulata. In the basal ganglia, there exist both a direct and an indirect pathway. The direct pathway involves striatal outflow that directly inhibits the globus pallidus and substantia nigra pars reticulate via dopaminergic (D1) receptors. The indirect pathway consists of inhibitory connections between the cortical striatum and the globus pallidus, between the globus pallidus and the subthalamic nucleus via dopaminergic (D2) receptors.1,2

The subthalamic nucleus provides excitatory influence on both the global pallidus and the substantia nigra, both of which provide inhibitory influence on the ventral lateral nucleus of the thalamus. Dopamine secreted from the areas of the substantia nigra (pars compacta) activates the direct pathway and inhibits the indirect pathway. Decreased dopamine secretion from damaged neurons in PD results in increased inhibitory output via both these pathways.

Lewy Body Diseases

Lewy body diseases include PD, PD with Dementia (PDD) and Dementia with Lewy bodies (DLB). While Lewy bodies are found in Alzheimer’s disease (AD), AD is generally considered as distinct from other Lewy body diseases. Other disorders where Lewy bodies are occasionally found include atypical parkinsonism and Pantothenate kinase-associated neurodegeneration (PKAN) (formerly known as Hallervorden-Spatz disease). Dementia with 9 ce4less.com ce4less.com ce4less.com ce4less.com ce4less.com ce4less.com

Lewy bodies is the second most common form of dementia after Alzheimer’s disease. There is considerable overlap in these disorders. In PD, the Lewy bodies are found primarily in the brain stem. In DLB, there is a more widespread distribution of Lewy bodies and DLB is often accompanied by symptoms of PD parkinsonism.1-3,12

Lewy body diseases can cause alterations in levels of alertness and attention, hallucinations, muscle stiffness, confusion, memory loss, movement disorders and postural dysfunction.12 Lewy bodies are spherical or ovoid aggregations of protein found in a number of disorders including Parkinson’s disease and Lewy body dementia. They are occasionally found in Pick’s disease, corticobasal degenerations and multiple system atrophy. The Lewy body itself is composed of aggregates of alpha-synuclein and other proteins including ubiquitin, neurofilament protein, alpha B crystallin and tau protein.

It is believed that impaired protein degradation pathways such as the ubiquitin-proteasome and the autophagy-lysosome pathways play an important role in these inclusion bodies. Morphologically, Lewy bodies can be divided into cortical and brainstem types. Brainstem Lewy bodies are characterized by hyaline eosinophilic cores, concentric lamellar bands and narrow pale halos. These contain both alpha-synuclein and ubiquitin most commonly. Cortical Lewy bodies, commonly found in the cerebral limbic cortex and the amygdala tend to lack a halo and tend to contain less alpha- synuclein than do the brainstem Lewy bodies. Dementia with Lewy Bodies is a progressive and degenerative disease with dementia generally preceding any motor symptoms.12,14 There are several clinical features found in DLB that can provide clues distinguishing between

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• Variations in cognitive functions - Excessive daytime drowsiness - Staring without focus for long periods of time - Episodic speech disorganization • Motor dysfunction is Parkinsonian - Most commonly, the motor dysfunction shows parkinsonian signs, but these are insufficient to diagnose PD • Early occurring extrapyramidal symptoms • Both visual and (less commonly) non-visual hallucinations - Delusional thinking can also occur in DLB • Anterograde memory loss - Anterograde memory loss is a prominent early sign of Alzheimer’s demetia • Visuospatial impairment • Executive function deficits

Pathologic Findings Of Parkinson’s Disease

To date, there is no widely accepted criteria for the diagnosis of PD. The major pathologic findings in PD remain 1) decreased numbers of pigmented dopaminergic neurons, predominantly in the substantia nigra pars compacta via one or more (or unknown mechanisms) as described above, and 2) histologic finding of Lewy bodies and Lewy neurites. Decreased striatal dopamine allows for an increased inhibition of the basal ganglia- thalamocortical motor circuit via both glutamate and GABA signaling. The increased inhibitory output from the globus pallidus and the substantia nigra pars reticulate results in impaired movement. This section discusses the

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Parkinson’s disease is among the most common neurodegenerative disorders, affecting approximately 120 per 100,000. Some estimates range as high as 330/100,000. Since PD is a clinical diagnosis, there is some uncertainty regarding prevalence and incidence, but it is known that both prevalence and incidence increases with age and is about one and a half times more common in men than in women.

Nonmotor versus Motor Symptoms

Non-motor symptoms often appear before motor symptoms. Non-motor symptoms are listed below. • Pain • Fatigue • Hyposmia • Excessive salivation • Forgetfulness • Sleep disturbances: Loss of atonia during sleep, and acting out dreams by kicking, talking, crying, moaning during sleep, and Rapid Eye Movement Behavior Disorder (RBD) • Mood disorders • Erectile dysfunction • Urinary urgency • Autonomic dysfunction: Constipation, sexual dysfunction, and abnormalities in sweat function • Seborrheic dermatitis

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• Difficulties with activities of daily living: Getting dressed, using the bathroom, getting out of the car or out of a chair

The most common initial motor symptom is a resting tremor in an upper extremity. The tremor is generally asymmetric. Other early findings include progressive bradykinesia, difficulty with gait and rigidity. The same-side lower extremity may drag. Other early motor symptoms include micrographia (progressively shrinking or smaller handwriting), postural instability and impairment of dexterity. There may also be a decreased arm swing on the first-involved side, a softened voice. Based on a recent systematic review of clinically heterogenous clinical studies evaluating the diagnosis of PD in over 7,600 patients, researchers have found an accuracy of 83%, sensitivity of 89.5% and specificity of 68.3%. Expert clinicians had an accuracy rate of 83.9% while non-experts had an accuracy rate of 73.8%.

The cardinal motor symptoms of PD are rest tremor, bradykinesia and rigidity. These motor symptoms are considered to be a direct result of the loss of dopaminergic neurons, primarily in the substantia nigra pars compacta and reticulata, but also in other areas of the brain. The non-motor features of PD may result from multiple neurotransmitter deficiencies in both the central and peripheral nervous systems. These non-motor symptoms include autonomic, psychiatric, cognitive, sensory and sleep disorders. The non-dopaminergic neurotransmitters involved include cholinergic, adenosinergic, glutamatergic, GABAergic, noradrenergic, serotonergic, opioidergic, and histaminergic systems. While these pathways are only beginning to be explored, understanding the effects of these alternative neurotransmitters may provide potential pharmacological targets.

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Table 1: Neurotransmitters involved in Parkinson's Disease and Potential Pharmacological Approaches.

Neurotransmitter Associated Symptom Potential drug(s)/Targets

Acetylcholine • Posture/Gait dysfunction • Cholinesterase inhibitors • Gait freeze • Nicotinic receptor agonists • Cognitive issues

Adenosine • Motor dysfunction • Adenosine A2A receptor • Dyskinesia antagonists • Caffeine

GABA • Motor dysfunction • GAD genes • Dyskinesia

Glutamate • Dyskinesia • NMDA receptor • Gait freeze antagonists • AMPA receptor antagonists • Glutamate receptor negative allosteric modulators

Histamine • Dyskinesia • H2 receptor antagonists

Noradrenaline • Balance/Gait dysfunction • Methylphenidate, �2 • Gait freeze receptor antagonists • Dyskinesia

Serotonin • Motor disturbances • 5-HT1A receptor • Dyskinesia antagonists

Staging schemes, based on autopsy results, suggest that the earliest pathology occurs in the dorsal motor nucleus of the vagus and olfactory bulbs, then it spreads through the locus coeruleus and the substantia nigra. Thereafter it progresses to the basal forebrain, amygdala, the medial temporal lobe and finally the cortical areas of the brain. However, this does not appear to apply to all or even most cases and is not based on any 14 ce4less.com ce4less.com ce4less.com ce4less.com ce4less.com ce4less.com longitudinal studies. What is becoming more evident is that PD is a heterogeneous disorder. This has led to proposals to divide PD into two sub- types: 1) Tremor-dependent PD, which occurs earlier (20-40 years), has a slower progression, has a genetic basis, and responds well to pharmacological treatment, and 2) Postural Instability and Gait Difficulty PD, which involves sporadic occurrence, generally after the age of 60, with bradykinesia and rigidity as the dominant symptoms, and neuropsychiatric symptoms, such as depression and dementia that occur earlier in the disease process.

Tremor

The tremor in PD is an asymmetric resting tremor, which disappears during sleep and diminishes during motion. Patients will often describe the tremor as a shakiness or nervousness. The tremor often begins in the thumb or fingers, or less commonly in the forearm or wrist. The resting tremor in PD appears to be due to the firing of dopaminergic neurons that result from the loss of dopamine secretion. The Movement Disorder Society has characterized three subtypes of tremor.

1. Resting tremor - occurs at a frequency between 4 and 6 Hz, disappears with voluntary movement, and is relatively specific for PD 2. Resting tremor with essential tremor - has a higher frequency than the resting tremor and may be postural or kinetic (action), and can affect the arms, hands, head, larynx, tongue and chin 3. Postural and kinetic (action) tremors

More recent classifications define “action” and “resting” tremors. Action tremors include postural, kinetic and intention tremors. Table 2. Types of Tremors

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TYPE OF TREMOR

ACTION Postural Occurs as a patient maintains a voluntary position against gravity, i.e., arms outstretched

Kinetic Occurs as a patient performs any voluntary movement.

Intention Occurs with purposeful movement towards a target. Generally, worsens as target is approached. Subtypes include task-specific tremors (writing/speaking).

Isometric Occurs with a voluntary muscle contraction done without any movement

REST Occurs when muscles are relaxed. Pill-rolling tremor is often seen in patients with PD

A patient may be diagnosed with PD even though tremor is not present; however, tremor appears in approximately 70% of patients with PD. After varying periods of time, the tremor may spread to the ipsilateral lower extremity or, more rarely, to the contralateral upper extremity. Other characteristics of tremor are that tremor increases with stress and anxiety and tremor is absent during sleep.

Rest tremors are often more severe opposite to the side of the worse bradykinesia, but the amplitude of the tremor does not correlate with deficiencies of dopaminergic neurons and does not completely respond to dopaminergic medications and treatment. In addition, the primary tremor pacemaker is not known. Recent studies have suggested that tremor arises first in the basal ganglia, propagating to the cerebello-thalamo-cortical circuit. Another model hypothesizes a globus pallidus - sub-thalamic nuclear pacemaker, a synchronized basal gangliar-thalamocortical loop and the cerebellar dentate-thalamocortical circuits as playing major roles in producing rest tremors.

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Bradykinesia

Bradykinesia is the slowing of movement. Bradykinesia is an ongoing process, while alternative terms such as akinesia indicates a failure of voluntary, spontaneous movement or associated movements. Hypokinesia refers to smaller than usual or desired movements. Bradykinesia may impair whole body movements and may be demonstrated during rapid, alternating movements of the fingers, hands or feet. Bradykinesia is characterized by a progressive reduction in both speed and the amplitude of the motion. Bradykinesia can also be recognized by loss of facial expression, decreased rate of blinking, changes in speech (monotonic or hypotonic), increased drooling due to decreased swallowing, a loss of spontaneous gestures, shortened stride, and a reduced arm swing when walking. It is believed that the bradykinesia seen in PD is due to failure of output from the basal ganglia to moderate both the preparation and the execution of movement.

Movement preparation deficits are characterized by slower reactions times as well as electroencephalogram (EEG) changes indicating deficits in the retrieval of stored “muscle memory”. EEG activity is characterized by predominant alpha (10Hz) and beta (20-30Hz) peaks with a delay of about 1 second. In addition, beta desynchronization is reduced in PD patients, an effect that can be stabilized by dopaminergic stimulation. While PD patients are not taking levodopa, EEG recordings indicate that there exists a coupling between areas of the brain (basal ganglia, cortex, subthalamic nucleus, internal segment of the globus pallidus); when levodopa therapy is resumed, these areas become decoupled. This has led to more tailored approaches to deep brain stimulation treatments — the question being whether stimulation of the subthalamic nucleus, the internal segment of the globus pallidus or both is most effective in PD patients.

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Movement execution deficits include deficiencies in maximal voluntary contractions as well as abnormalities in ballistic movement. Ballistic movement can be characterized by three-phased electromyographic pattern; an agonist burst, an antagonist burst and a final agonist muscle burst. In PD, the first agonist burst is reduced. In addition, increased fatigue, particularly with repetitive movements, is evident in these patients.

Rigidity

Muscular rigidity is another frequent finding in PD. The PD rigidity is characterized by an increased muscle tone at rest, a reduced reaction to passive movement, an increased resistance to stretching and an easing of the shortening reaction. Parkinson's disease rigidity is more noted in the flexor rather than the extensor muscles as it is during slow as opposed to fast stretching.

The cogwheel phenomenon, a circular jerking rigidity that continues throughout movement, may be a result of switches between rigidity and tremor. Rigidity in PD may be caused by changes in abnormalities in sensory inputs, changes in passive mechanical properties, increased stretch-evoked reflexes involving spinal or supraspinal activity.

Dyskinesia and Motor Fluctuations

Dyskinesia can be defined as choreic, ballistic or dystonic and are involuntary movements. These can be further classified into peak-dose, diphasic and square-wave (off-period) forms of dyskinesia, referring to medication-induced dyskinesia. Dystonias, on the other hand, are sustained muscle contractions and frequently cause abnormal postures including twisting movements. 18 ce4less.com ce4less.com ce4less.com ce4less.com ce4less.com ce4less.com

Dyskinesia types are highlighted here.

• Square-wave or off-period dyskinesia occurs before l-dopa therapy becomes effective or very low plasma levels. It commonly occurs in the foot as a spasm or an abnormal posture. • Diphasic dyskinesia occurs when once therapeutic levels of l-dopa are rising or falling. Diphasic dyskinesia often by rigidity or ballistic movement of the lower limbs. • Peak-dose dyskinesia may accompany l-dopa levels at their peak levels and is usually found in upper limbs.

Motor fluctuations can be of a number of different types including:

• Wearing-off: Occurs before a scheduled l-dopa dosing. • Delayed-on: Refers to an increased latency period between dosing (l- dopa) and effectiveness • Partial-on: Refers to a partial response to l-dopa • No-on: Refers to non-responsiveness to l-dopa • On-off: Refers to a fluctuating response to l-dopa

Dyskinesia and motor fluctuations are believed to be due to both central and peripheral mechanisms. The central mechanisms, which may all function at the same time, include:

• The progressive neuronal degradation reduces the “storage capacity” for dopamine in the synaptic vesicles • Aberrant release of dopamine by seratonergic neurons • Changes in dopaminergic receptors including supersensitivity, desensitization and downregulation • Increased glutaminergic activity

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Peripheral mechanisms explaining dyskinesia and motor fluctuations may include:

• Competition for protein carriers for l-dopa across the blood-brain barrier • Autonomic dysfunction may delay gastric emptying and thereby decrease l-dopa absorption

Management of dyskinesia and motor fluctuations can include modifying dosing schedules with smaller, multiple doses of l-dopa, using controlled- release dopamine agonists (i.e., amantadine), adding dopamine agonists, utilizing trans-dermal delivery systems and using either monoamine oxidase- B inhibitors or catechol-O-methyltransferase inhibitors, using botulinum toxin or using deep brain stimulation (DBS).

Balance, Posture and Gait Disturbances

Balance, posture and gait disturbances have perhaps the greatest effect on quality of life in patients with PD. These disturbances contribute to the risk of falls and subsequent fractures, decrease social interactions, and underlie the classic appearance of individuals with PD, including the stooped appearance, rounded shoulders and flexion of knees and hips. A significant number of patients can develop more serious postural deformities such as scoliosis, Pisa syndrome, antecollis, camptocormia and others.

A number of different central and peripheral mechanisms have been hypothesized to explain the postural deformities present in PD. These include a combination of rigidity, abnormal spatial recognition, asymmetry of messages from the basal ganglia, myopathy of spinal muscles, abnormal processing of proprioceptive or vestibular afferent signals and side effects of medications. 20 ce4less.com ce4less.com ce4less.com ce4less.com ce4less.com ce4less.com

Gait and balance disorders often do not respond to dopaminergic or other drugs and are not well understood. Animal studies have revealed a mesencephalic locomotor region that interacts with the basal ganglia, cerebellum and cortex with efferent pathways to the descending reticulospinal and the ascending thalamocortical pathways. An indirect pathway from the frontal cortex to the basal ganglia to the mesencephalic locomotor region has also been described, but the interactions and controls are not yet clear.

In early PD, the decrease in gait speed and stride length (hypokinetic gait) may be due to early effects of bradykinesia. In progressive PD, bradykinesia is insufficient to explain the dysfunction and may be due to the effect of perturbations in multiple pathways and multiple neurotransmitters, most recently, disturbances in the cholinergic neurotransmitters have been described, potentially leading to pharmacologic interventions.

Freezing of Gait

Freezing of gait (FOG) may be characterized by a difficulty in step initiation or start hesitation and episodes of unintended stoppage during gait. These episodes may include reduction in step size, resulting in a shuffling gait, a feeling or sense that the feet are glued to the ground and trembling knees. Triggers for FOG include change of environment (i.e., change in direction, change in level of flooring, narrow doorways, crowds, change in surface type etc.), dual tasking and emotional factors. FOG is common, especially in advanced cases of PD though it can occur earlier in the disease process. FOG is also associated with an increased frequency of falls and fractures as well as a decreased quality of life, anxiety and depression.

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As with the other signs and symptoms of PD, the pathology of FOG is not well understood, with several models being proposed to explain the occurrence of FOG. FOG responds poorly to dopaminergic therapy and to DBS, indicating that other areas of the brain beyond the circuits already described must be responsible for the dysfunction. FOG may be due to amyloid deposition, the loss of cholinergic neurons of the pedunculopontine nucleus (PPN), impaired visuospatial ability, and impaired coupling with step initiation and postural control.

More recently, multisystem pathologies have been postulated. These models incorporate physical, cognitive, attention and executive functions. The interference model postulates that FOG is a consequence of cognitive overload due to the breakdown of communication networks between parallel circuits of the cognitive, motor, and limbic circuits interrupting the motor pathways. A cognitive model postulates impaired decision-making processes that generate incorrect responses due to executive dysfunction. Newer understanding of FOG is likely to incorporate non-motor functions increasingly as it is becoming more evident that dysfunction in cognitive and executive functions can be correlated to FOG in PD.

Mood and Impulse Control Disorders

Depression, anxiety and other disorders such as impulse control disorders are common in PD. Depression affects 50-70% of patients and is based to varying degrees on the loss and degeneration of noradrenalergic and seratonergic neurons. Depression in PD is often unrecognized and negatively impacts outcomes as well as the quality of life. A recent systematic review and meta-analysis of 21 studies found that the prevalence of major depression was 22.9%. Tools for detecting depression in PD patients were also evaluated, such as the Geriatric Depression Scale (GDS), Beck

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Depression Inventory, Montgomery-Åsberg Depression Rating Scale, and the Unified Parkinson's Disease Rating Scale.

A recent systematic review of factors associated with the development of depression and anxiety concluded that motor fluctuations and the presence of autonomic symptoms were significantly associated with depression and anxiety in all studies. Age of onset (<60 years) and the severity of symptoms was variably significant. There was no significant correlation of depression and anxiety with laterality of motor symptoms or anti-Parkinson medications or therapies.

Impulse control disorders important in PD included sexual behaviors, compulsive gambling, eating and shopping. Other impulse control disorders have also been linked to dopamine-replacement therapy in PD. These include dopamine dysregulation syndrome (DDS), punding (repetitive, purposeless behaviors, characterized by an intense preoccupation with specific items or activities (i.e., collecting, arranging, or taking apart objects”)), hobbyism (i.e., excessive, repetitive exercise, projects), walk- abouts (aimless wandering), and hoarding (acquisition or failure to discard various low-value items). These Impulse control disorders, not all of which can be found in the DSM-5, can be defined as repetitive, excessive and compulsive.

Impulse control disorders have a number of similarities to drug addiction and other behavioral addictive disorders. Studies suggest that the prevalence in PD patients is higher than in the general population and appear to be correlated with the use of dopamine replacement therapy and dopamine agonists. The impulse control disorders in PD have also been correlated with a past or current history of smoking, a personal or family history of gambling or alcoholism, gender (male) and early onset.

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Rapid Eye Movement Behavior Disorder

In Rapid Eye Movement Behavior Disorder or RBD, individuals appear to “act out” dreams by physically moving their limbs, sleep walking, sleep talking, shouting, moaning, punching, waving their hands, kicking their legs and other physical activities. In a recent update of a 1996 report that documented that 38% of those with RBD converted to a parkinsonian disorder, the authors reported that 81% of males with RBD converted to a parkinsonian disorder or dementia. The interval of onset from RBD to parkinsonism ranged up to 29 years, with a mean of 14 years. Of the 21 patients followed, 13 were diagnosed with PD, 3 were diagnosed with Dementia with Lewy bodies, 2 with multiple system atrophy, 2 with Alzheimer’s disease and 1 with an unspecified dementia.

Diagnosis Of Parkinson’s Disease: A Review

The Movement Disorder Society has identified three motor manifestations of Parkinson’s disease, which are bradykinesia, in combination with either resting tremor, rigidity, or both.1,59,68-70 The centrality of motor symptoms for clinical diagnosis of PD are generally well-defined; however, non-motor symptoms can often predominate a clinical presentation and are acknowledged. When non-motor features predominate, the diagnosis classification is prodromal Parkinson’s disease. There are four cardinal signs of Parkinson’s disease that must be identified and are defined as resting tremor, rigidity, bradykinesia, and postural instability. Postural instability is not required for a diagnosis of PD, and commonly arises later in the disease process.

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Resting Tremor

Resting tremor is assessed by having patients seated with their arms relaxed on their laps. The resting tremor may be observed without further instructions, or it may be triggered by asking the patient to count backwards from ten. Kinetic or postural tremor may be present but is not required as part of the diagnostic criteria. Kinetic tremor may be observed in the finger- to-nose test while postural tremor may be observed by having patients hold their arms out in front of themselves.

Rigidity

Rigidity is the “slow passive movement of major joints with the patient in a relaxed position and the examiner manipulating the limbs and neck.”68 This form of rigidity is the “lead-pipe” form exemplified as velocity-independent resistance to passive movement. The cogwheel phenomenon is often present (so-named because of its cogwheel-like jerks to passive movement), but lead-pipe rigidity must be present as well to fulfill the minimum requirements of rigidity.

Bradykinesia

The bradykinesia of PD requires a slowness of movement and a decrease in amplitude or speed of movement. Limb bradykinesia must be present to establish PD. Evaluation of bradykinesia may be accomplished by finger- tapping, protonation-supination, hand movements, toe or foot tapping, and postural instability.

Postural instability, identified later in the disease process, can be tested using the retropulsion test. This test involves the patient being asked to stand with arms at their sides and eyes open. The patient is also told that this is a balance test and they will be caught if they begin to fall or unable to 25 ce4less.com ce4less.com ce4less.com ce4less.com ce4less.com ce4less.com regain their balance. The examiner stands behind the patient and pulls back on the shoulders. One or two steps to regain balance are considered normal.

The Movement Disorder Society (MDS) proposed to redefine Parkinson’s disease in 2014. A number of critical issues were identified and discussed.1,59,68-70

• New findings challenge the central role of the classical pathologic criteria as the arbiter of diagnosis, notably genetic cases without synuclein deposition, the high prevalence of incidental Lewy body (LB) deposition, and the nonmotor prodrome of PD. It remains unclear, however, whether these challenges merit a change in the pathologic gold standard, especially considering the limitations of alternate gold standards. • The increasing recognition of dementia in PD challenges the distinction between diffuse LB disease and PD. Consideration might be given to removing dementia as an exclusion criterion for PD diagnosis. • There is increasing recognition of disease heterogeneity, suggesting that PD subtypes should be formally identified; however, current subtype classifications may not be sufficiently robust to warrant formal delineation. • The recognition of a nonmotor prodrome of PD requires that new diagnostic criteria for early-stage and prodromal PD should be created; here, essential features of these criteria are proposed. • There is a need to create new MDS diagnostic criteria that take these changes in disease definition into consideration.

The MSD task force made the following proposals related to standards of diagnosis.1,59,68-70

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• The core clinicopathologic criteria of a clinical motor syndrome accompanied by SNpc neurodegeneration and synuclein deposition remain a gold standard of PD diagnosis. In the future, should reliable biomarkers of synuclein deposition be developed, these can be used to indicate a likely gold-standard clinicopathologic diagnosis.

• To incorporate genetic findings under the PD umbrella, a separate “clinicogenetic” category should be created to diagnose PD, regardless of the occurrence of synuclein deposition. This category would refer specifically to highly penetrant mutations in which the majority of affecteds meet clinical PD criteria, regardless of whether autopsy specimens of patients with this mutation find a-Syn pathology. In research studies, this diagnostic subcategory could be included or not according to the context. For example, an autopsy study validating clinical diagnostic criteria might exclude such patients, a randomized trial of symptomatic dopaminergic therapy might include them, and a neuroprotective trial may elect to include or exclude, depending upon the mechanism of the agent.

• A new scheme is likely needed to replace the current PARK classification, which is under considerable strain. This scheme should specifically differentiate between causative genes and risk factors, consider the predominant phenotype, and — in the long run — admit the incorporation of protective variants.

One-Year Rule

In the past, if dementia was diagnosed before the second year after diagnosis of Parkinson’s disease, the 1-year rule excluded PD and dementia with Lewy Bodies (DLB) was the correct diagnosis. The MDS task force

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Subtypes Of Parkinson’s Disease

No currently accepted subtypes of Parkinson’s disease exist even though there is a considerable variability in the appearance and progression of motor symptoms and a high prevalence on non-motor symptoms. The MDS task force proposed that:1,2,59,68-70 • Clinical subtypes should only be delineated if there are clear data that demonstrate consistent, large differences in prognosis, predicted disease manifestations, or treatment. Currently, it is unclear whether any of the current subtype classifications qualify. • The search for subtypes should not be restricted to clinical features, but should include subtypes of molecular pathogenesis.

Onset of Parkinson’s Disease

The motor symptoms of PD may sometimes be preceded by many years of non-motor symptoms, such as idiopathic rapid eye movement sleep behavior disorder (RBD), hyposmia (reduction in smelling), autonomic symptoms (constipation), depression, and a showing of abnormal neuroimaging results without any clear symptoms of PD. The MDS task force proposed that the clinical diagnosis of classic PD should remain centered on a motor

28 ce4less.com ce4less.com ce4less.com ce4less.com ce4less.com ce4less.com syndrome.1,2 Further, separate research-based criteria should be developed to allow diagnosis of early PD stages.

For delineation of early stages, disease should be classified as preclinical and prodromal.1,2,109 Preclinical refers to the presence of neurodegenerative synucleinopathy without clinical symptoms (i.e., defined by biomarkers). This stage cannot be diagnosed currently because reliable biomarkers are not available. Prodromal refers to the presence of early symptoms and signs before the classical PD diagnosis is possible. This prodromal term makes no assumptions about the order in which motor versus non-motor symptoms develop.

Because one cannot determine whether any patient with prodromal neurodegenerative synucleinopathy will eventually progress to full, clinical PD, the definition of prodromal PD should center upon the likelihood of a neurodegenerative synucleinopathy being present, regardless of “conversion rate” to full clinical PD. Although PD, by definition, passes inevitably through some type of prodromal phase, there are currently no 100% reliable means to identify prodromal PD. Therefore, diagnostic criteria for prodromal PD will necessarily be variable and based on probabilities.

Two levels of certainty to diagnose PD have been proposed. Probable prodromal PD would refer to a high likelihood (i.e., >80%, sufficiently certain for neuroprotective trials). Possible prodromal PD would refer to a lower, but still substantial, likelihood of neurodegenerative synucleinopathy (i.e., 30% -80%). Prodromal PD criteria should incorporate clinical motor markers, clinical nonmotor markers, and nonclinical biomarkers. Inclusion of a marker into prodromal criteria should generally require prospective studies documenting predictive value for full clinical PD. Markers should be divided into categories of specificity, such that high specificity markers carry more 29 ce4less.com ce4less.com ce4less.com ce4less.com ce4less.com ce4less.com weight than those with lower specificity. Criteria should also incorporate risk, adjusting probability estimates for persons with documented high-risk states (i.e., carriers of genetic mutations).

Treatment Of Parkinson’s Disease

In 2015, the Movement Disorder Society extended their diagnostic criteria for Parkinson’s disease. Diagnosis of established Parkinson’s Disease requires absence of absolute exclusion criteria, at least two supportive criteria, no red flags. The medical management of Parkinson’s disease is largely symptomatic, providing control of signs and symptoms while, ideally, minimizing adverse reactions. Motor symptoms, motor complications and non-motor symptoms as well as psychiatric and mental health issues all need to be treated. Dopamine deficiency is addressed in early PD while non- dopaminergic effects and dopaminergic-resistance develop later in the disease process, resulting in both motor and non-motor symptoms. Symptom Progression and Medication

Medication should be instituted when patients are experiencing functional impairment or social difficulties.1,2,76 Motor symptoms can be treated with a number of different medications. The most well-established medications are reviewed in this section, and include the levodopa drugs, commonly given along with peripheral dopa decarboxylase inhibitors (PDDIs). This class includes levodopa-carbidopa and levodopa-benserazide. Other well- established classes of drugs include dopamine agonists (pramipexole, ropinirole and rotigotine), the monoamine oxidase type B inhibitors (MAOBIs such as selegiline and rasagiline) and as adjunct therapies the catechol-O- methyltransferase inhibitors (COMTIs) that include entacapone and tolcapine.75-84

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Levodopa and dopamine agonists can be used to treat all motor symptoms. MAOBIs may be particularly useful with early, mild symptoms of PD as well as motor fluctuations while the COMTIs are useful for motor fluctuations.

Other medications, for which the evidence is much less established, include amantadine (used primarily for gait dysfunction and dyskinesia), β-blockers such as propranolol (to treat tremors), anticholinergics (i.e., trihexyphenidyl, Benztropine, also used to treat tremor) and the neuroleptics such as clozapine used to treat both tremor and dyskinesias.

Initially, one must determine the greatest disability - and the degree of disability - when determining treatment approaches. Often, a monoamine oxidase type B inhibitor such as selegiline or rasatiline should be considered. The use of dopamine agonists can delay the motor complications seen in younger patients. In older patients, the use of dopamine agonists is associated with a greater risk of neuropsychiatric complications.

The European Federation of Neurological Societies (EFNS) and the Movement Disorder Societies (in Europe) have produced guidelines on the therapeutic management of Parkinson’s disease. Their recommendations for the treatment of early PD are listed below, as well as common medications and their adverse effects. The first step in defining the optimal treatment for individual PD patients is to determine the source of the greatest disability: tremors, bradykinesia with impaired dexterity or postural instability with gait impairment. Secondarily, the age of the patient is important in determining the optimal evidence-based treatment approach.

For patients who are severely impaired by their symptoms, multiple large trials have established that levodopa is associated with fewer adverse effects such as freezing, sleep difficulties, psychotic episodes or impulse control disorders as compared to other medications such as dopamine agonists. On 31 ce4less.com ce4less.com ce4less.com ce4less.com ce4less.com ce4less.com the other hand, dopamine agonists are less likely to cause motor complications such as dyskinesia. Recent studies have indicated, in addition, that over the long term, any advantage of dopamine agonists as compared to levodopa is lost over time. In addition, there is some evidence of benefit in using MAOBIs (monoamine oxidase type B inhibitors) in early PD with mild symptoms.

Levodopa (along with a dopa decarboxylase inhibitor) is titrated slowly, starting at a low dose. A common dosage is 300-600 mg/day in divided doses (usually three to four). Higher doses are avoided as they can lead to the development of dyskinesias. If nausea is a problem, the medication can be taken with food. MAOBIs can also be added to the early treatment regimen. Selegiline is generally used as an adjunct to levodopa while rasagiline has been successfully used as monotherapy in early PD, though it is also useful as an adjunct.

Dopamine agonists such as pramipexole and ropinirole have been suggested to delay the need for levodopa and to delay the appearance of motor symptoms. However, the early used of dopamine agonists as monotherapy is rather limited due to a higher number and sometimes degree of adverse effects such as sleepiness, hallucinations and impulse control disorders. Dopamine agonists may be more beneficial in younger patients (i.e., less than 70 years old) with no apparent cognitive difficulties. Initial low doses should be titrated slowly and cautiously to obtain symptom relief.

Anticholinergic agents may provide good control of tremor in some patients. But there is a good deal of variability in the response of individual patients to individual anticholinergic agents. In addition, the cognitive and memory side effects can be unacceptable, particularly in an elderly patient. Amantadine is an antiviral drug. It is not clear how amantadine functions in PD, but it may 32 ce4less.com ce4less.com ce4less.com ce4less.com ce4less.com ce4less.com potentiate the dopaminergic response. Amantadine may also increase the release of stored dopamine and norepinephrine.

The choice of drug depends on the impact of improving motor disability.

Options:

• MAO-B inhibitor (selegiline, rasagiline) (Level A evidence) • Oral or transdermal dopamine agonist. Pramipexole, piribedil, ropinirole and rotigotine are effective (Level A evidence). Initial treatment with an agonist can be recommended in younger patients (Good Practice Point, GPP). • Ergot derivatives are not recommended as first-line medication because of the risk of fibrotic reactions. • Levodopa is the most effective symptomatic drug (Level A evidence). • Controlled-release formulations or adding entacapone is not effective in the delay of motor complications (Level A evidence) • Amantadine or an anticholinergic (Level B evidence) • Rehabilitation: because of the lack of evidence in early-stage disease, a recommendation cannot be made

Practical Recommendations in patients without motor complications:

Patients not on dopaminergic therapy: If a patient has started on an MAO-B inhibitor, anticholinergic, amantadine or a combination of these, a stage will come when there is a requirement for adding levodopa or a dopamine agonist (GPP)

Patients on dopaminergic therapy: If on dopamine agonist therapy, increase the dose (GPP), switch between agonists (Level C evidence), and add levodopa (GPP). If on levodopa, increase dose (GPP), add agonist (GPP), and add COMT inhibitor (GPP).

Patients with disabling tremor: If significant tremor persists, consider anticholinergics (GPP), clozapine (Level B evidence), beta-blockers (propanolol), and deep brain stimulation.

All the medications carry some risk of adverse effects. Treatment is symptomatic and titration is recommended for levodopa. Currently, there are no definitive neuroprotective approaches or disease-modifying therapies. In some cases, shortening dose intervals and keeping individuals at the 33 ce4less.com ce4less.com ce4less.com ce4less.com ce4less.com ce4less.com lowest dose possible may postpone motor complications while adding adjunctive treatment may improve symptomatic control.

Common Medications: Adverse Effects, Typical Dosing, Potential Adjunct Therapy

Medication Adverse Effects Typical Dosing Can be used as Adjunct Therapy Levodopa-PDDI • Nausea Initial titration to 100/25mg Y • Dyskinesia 3x/day. • Orthostatic Increase based on symptoms. hypotension Maximum ~ 1500/375 mg per day • Hallucinations Dopamine • Nausea • Pramipexole: 0.125 mg/d (tid) Y agonists • Dyskinesia • Pramipexole, ER: 0.26 mg, 0.52 • Orthostatic mg, 1.05 mg, 2.1 mg, or 3.15 hypotension mg (qd) • Hallucinations • Ropinirole: 0.25 mg (tid). Max~ • Impulse control 24 mg (qd) disorders • Ropinirole ER: 6-24 mg (qd) (ICDs) • Rotigotine: Initial dose: 2 mg/d. • Edema Max~ 24 mg/d • Sleep problems MAOBIs • Exacerbation of • Selegiline: 2.5 mg/day. Max~ Y levodopa’s 5mg (bid) adverse effects • Rasagiline: 1 mg/day • Stimulation • Headache Buccal selegiline and rasalinine are • Arthralgia not metabolized to amphetamine • Depression while the oral forms of these • Dizziness medications are. COMTIs • Dark urine • Entacapone: 200 mg with each Y • Exacerbation of dose of levodopa. Max 8/day levodopa • Tolcapone: 1-200 mg (tid) effects • Hepatotoxicity Levodopa/carbidopa/entacapone may shorten time of onset of dyskinesia with no wearing-off Amantadine • Hallucinations Initial dose: 100mg/d. Max~ 100 Sometimes • Confusion mg qid effective as • Blurred vision an adjunct. • Edema Evidence for • Nausea amantadine • Dry mouth is mixed. The • Constipation EFNS stated amantadine to be effective as symptomatic 34 ce4less.com ce4less.com ce4less.com ce4less.com ce4less.com ce4less.com

therapy or as an adjunct. β-blockers • Dizziness Initial dose: 40 mg (bid). Max~ Conflicting • Fatigue 320 mg/day evidence for usefulness as an adjunct treatment. Anticholinergics • Hallucinations • Trihexyphenidyl: Initial dose: Conflicting • Confusion 1mg/day. Maintenance: 2mg evidence for • Blurred vision (tid) usefulness as • Urinary • Benztropine: Initial dose: 0.5-1 an adjunct retention mg/day. treatment. • Nausea Primarily • Dry mouth anecdotal • Constipation information. Neuroleptic • Agranulocytosis Initial dose: 6.25- 12.5 mg at Possibly • Myocarditis bedtime. Max~ 150 mg/day effective for • Sedation tremor • Seizures • Orthostatic hypotension

Dopaminergic Neurons

Dopamine is a catecholamine neurotransmitter involved in major neural functions including mood, movement and learning. Dopamine is also implicated in addictions. Dopamine is synthesized from the essential amino acid, tyrosine. Tyrosine enters the dopaminergic neuron and is hydroxylated by tyrosine hydroxylase to form L-dopa. L-dopa is then decarboxylated by l- amino acid decarboxylase to form dopamine. Dopamine is then stored in synaptic vesicles in the presynaptic neuron.

There are three main systems of the brain populated with dopaminergic neurons: the nigrostriatal system, mesolimbic system, and mesocortical system.

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These neurons originate in the substantia nigra, terminating in the caudate nucleus and the putamen, both of which are located in the midbrain. The nigrostriatal system is an important control of movement and the area prominent in the pathology of Parkinson’s disease.

Mesolimbic System

These neurons originate in the ventral tegmental area, extending to areas of the limbic system, including the nucleus accumbens, the amygdala and the hippocampus. The mesolimbic system plays a central role in the reward system and in addictions

Mesocortical System

The mesocortical system originates in the ventral tegmental area and extends to the prefrontal cortex, impacting executive functions such as planning and problem solving as well as memory. Dopamine can be taken up by the post-synaptic neurons and re-taken up by the pre-synaptic neurons to be re-released. Dopamine may also be used in the synthesis of norepinephrine (via dopamine β-hydroxylase) and to epinephrine (via phenylethanolamine N-methyltransferase with S-adenosyl-L-methionine (SAMe) as a cofactor).

Dopamine is degraded by both isoforms of monoamine oxidase (A and B) and by catechol-O-methyl transferase (COMT) followed by aldehyde dehydrogenase (ALDH). The primary end product of this degradation is homovanillic acid (HVA). HVA is excreted primarily by the kidneys. Dopamine may also be oxidized resulting in quinones and free radicals - oxidative stress may be one of the causes of cell death in Parkinson’s disease.

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Main Functions of Dopamine

Dopaminergic neurons in the midbrain have a role in motivation and behavior. In addition, activation and inactivation of dopamine neurons regulate mood and induce reward and aversion, respectively. In general, increased activity increases reward while decreased activity may induce aversion.66

Dopaminergic neurons in the substantia nigra (primarily found in the pars compacta with fewer dopaminergic neurons found in the pars reticulata) project to the dorsal striata forming the nigrostriatal pathway. Here the dopaminergic neurons play a substantial role in controlling motor function and in the learning of new motor skills. The substantia nigra along with the ventral tegmental area form the primary dopaminergic areas of the basal ganglia, informing action selection, either by releasing inhibition to allow a specific behavior or movement or by maintaining that inhibition, allowing other or competing behavior or movement.

Dopamine plays a critical role within the reward system involving pleasure, learning and behaviors as well as aversion. These dopaminergic neurons are found in the ventral tegmental area which expresses heterogeneous dopaminergic neuronal populations with diverse axonal projections in addition to varied anatomical, molecular and electrophysiological features. In the hypothalamus, dopaminergic neurons project into the pituitary (forming the tuberoinfundibular pathway) where these neurons influence the secretion of prolactin from the anterior pituitary gland. Dopamine inhibits prolactin secretion.

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Dopamine Receptors

There are five dopamine receptor subtypes currently known (D1- D5). All five are members of the G-protein-coupled receptor (GPCR) superfamily with the canonical seven transmembrane structure. The members of the GPCR family, including all the dopamine receptor subtypes, can signal through G protein dependent and independent mechanisms. If coupled to Gαs,oif, cAMP production as a second messenger is stimulated. If coupled to Gαi/o, cAMP production is inhibited. D1 class receptors (D1 and D5) are coupled to Gαs,oif while D2 class receptors are coupled to Gαi/o. Dopamine receptors play a role in regulating voluntary movement, feeding behavior, addictions, sleep, mood, cognitive function, sense of smell, vision, reward, aversion, hormonal regulation, sympathetic regulation, parasympathetic regulation, immune response and cardiovascular, renal and gastrointestinal functions.66-70

Dopamine receptors can also utilize alternative signaling pathways. These include transactivation of brain-derived neurotrophic factor (BDNF) in neurons, regulation of calcium channels via direct protein-protein, via direct + + interaction with Na /K -ATPase and via IP3-mediated signaling. Additional pathways may be utilized including via the multifunctional adaptor protein β- arrestin and glucogen synthase kinase (GSK3).77,78

Dopamine receptors can function as homomers and as heteromers with several other receptors including other GPCRs, (eg. subtype D1 and D2 herterodimers) and with glutamate receptors. D1-D2 heterodimers recruits

Gαs,oif leading to calcium release. Both members of the heterodimeric group are required—dopamine or a combination of selective subtype agonists are needed to increase calcium release. However, inhibition of calcium release can be achieved with either a D1 or D2 receptor antagonist. A recent review 38 ce4less.com ce4less.com ce4less.com ce4less.com ce4less.com ce4less.com of the function of dopamine receptors concluded that “multidimensional analysis of dopamine receptor biology will eventually provide an opportunity for the precise targeting of desired components of post-receptor intracellular processes either via receptor-related mechanisms or post-receptor signaling cascades, thereby providing an exciting opportunity to target pathological processes with minimal propensity of developing side effects. Such approaches involving ‘biased agonism’, allosteric-based targeting of receptors and heteromers and downstream intracellular signaling events could eventually result in emergence of a new generation of dopamine receptor-based therapies for a variety of dopamine-related disorders.”78

After synthesis, dopamine is transported into vesicles by vesicular monoamine transporter (VMAT)-2. Dopamine is transported into presynaptic terminals by a dopamine transporter (DAT). Both DAT and VMAT-2 are regulated by post-translational modification, protein-protein interactions and by intracellular localization.80,120,124 It is believed that α-synuclein plays a role in regulating the function of DAT: α-synuclein appears to “recruit and stabilize DAT at the plasma membrane and to enhance Vmax under normal conditions.”80 It is hypothesized that in Parkinson’s disease, the overexpression of α-synuclein accelerates the uptake of dopamine by DAT: this leads to oxidative stress and terminal damage. In addition, decreases in VMAT-2 have been seen in postmortem studies. Interestingly, pesticides, polychlorinated biphenyls and brominated compounds, all associated with Parkinson’s disease, also are associated with damage to DAT and VMAT-2.

Managing Advanced Parkinson’s Disease

The effects or symptoms of Parkinson’s disease (PD) include motor fluctuations, dyskinesia (involuntary movement) with and without motor fluctuations, nausea, psychiatric comorbidities, and cognitive impairment. 39 ce4less.com ce4less.com ce4less.com ce4less.com ce4less.com ce4less.com

These effects are often caused by the medication prescribed to treat PD. These effects vary in severity making management complex and difficult at times.

Motor Fluctuations

Motor fluctuations are a common adverse effect to dopaminergic medications and may take months or years to develop. When assessing motor fluctuations, the clinician will record on periods, which are those times when a patient is experiencing good control of symptoms with the medication, and off periods, which are those times when the medication is wearing off or if symptoms are resurfacing. Levodopa-induced dyskinesia is present when levodopa doses are at their peak. In the absence of peak-dose dyskinesias, the approaches are relatively straightforward, as reviewed in the following sections.75-83,101-109

Increasing ‘On’ Times

The most common approaches to increasing ‘on’ times and/or decreasing ‘off’ times are to increase the dose of the dopaminergic agents, adding a second dopaminergic medication, and levodopa dose fractionation, where the levodopa dosage is decreased but given more frequently or with the addition of either a catechol-O-methyltransferase inhibitor (COMTI) or a monoamine oxidase type B inhibitor (MAOBI), which inhibit the catabolism of levodopa and dopamine. The evidence for the use of entacapone and tocapone indicates that these COMTIs can significantly reduce ‘off’ time, but have similar adverse effects including nausea, diarrhea, dyskinesia and orthostatic hypotension. For example, evidence has shown that COMTI, opicapone, as an adjunct to either dopamine agonists or MAOBIs, improved motor fluctuations in PD patients over 60 years of age.

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Enteral Suspension

An enteral suspension of carbidopa-levodopa that is infused into the jejunum was approved in 2015. By 12 weeks, the mean ‘off’ time for patients using the enteral suspension was decreased by 4.04 hours while the control group experienced an ‘off’ time of 2.14 hours. Mean ‘on’ time without dyskinesia increased by 4.11 hours in the intestinal group and 2.24 hours in the control group. In general, it is recommended that dopaminergic dosing can be increased to minimize ‘off’ time up to maximum dosage unless peak-dose symptoms such as dyskinesia appears.

Safinamide as an Adjunct Treatment

Safinamide is an MAOBI that was approved in 2017 as an adjunct treatment for ‘off’ periods in patients taking carbidopa-levodopa. The results of two Phase III trials (~1200 patients) indicated that safinamide decreased ‘off’ times and increased ‘on’ times without an increase in dyskinesia.

Dopamine Agonists

Apomorphine is a dopamine agonist that is useful in treating patients experiencing a sudden, akinetic episode. It can be administered parenterally. Injectable apomorphine has been approved in the U.S., for treatment of motor fluctuations in PD but apomorphine infusion pumps do not have Food and Drug Administration (FDA) approval. Apomorphine is particularly useful for patients who are under orders to take “nothing by mouth” or nil per os (NPO). The use of apomorphine requires a test dose before ongoing treatment. Lisuride is another dopamine agonist but it is not currently approved in the United States.

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Deep Brain Stimulation

Deep brain stimulation is a form of stereotactic neurosurgery, which commonly targets the globus pallidus internus (GPi) and the subthalamic nucleus (STN) in patients with advanced Parkinson’s disease. In deep brain stimulation or DBS, signals from affected parts of the brain are blocked. The DBS system has three components, the lead, the extension and the neurostimulator or battery pack, generally implanted under the skin near the collarbone.

In a 2-year trial involving 251 patients, DBS of the subthalamic nucleus, accompanied by medical therapy, was found to be superior to medical therapy alone. The mean age of the patients was 52 years, with a mean disease duration of 7.5 years. Outcomes were measured using the Parkinson's Disease Questionnaire (PDQ-39) summary index. In the PDQ-39, higher scores (rating from 0-100) indicated worsening function. In this intention-to-treat study, 124 patients were assigned to the DBS group (120 completed the study) and 128 patients were assigned to medical therapy only (123 completed the study). Major secondary outcomes such as motor disability, activities of daily living (ADL), the frequency of motor complications were improved in the DBS-plus-medical-therapy group as compared to the medical therapy alone group. However, the DBS group had a higher adverse event rate (54.8%) when compared to the medical therapy alone group (44.1%).

Another recent meta-analysis reviewing 6 trials with 563 patients found that DBS of the GPi or the STN were equally effective in improving motor function and activities of daily living. The analysis also found that DBS of the STN allowed for a greater reduction in medication while DBS of the GPi decreased the severity of psychiatric symptoms. A systematic review concluded that DBS of the STN and the GPi could improve gait and postural control but they 42 ce4less.com ce4less.com ce4less.com ce4less.com ce4less.com ce4less.com do not effect or they may aggravate dynamic postural control. In addition, DBS of the substantia nigra pars reticulata (SNr) and the pedunculopontine nucleus (PPN) had no effect on gait but improve anticipatory postural adjustments and gait postural control. Indications for deep brain stimulation include motor complications that are refractory to changing medications and/or dosage, lack of significant comorbidities, absence of symptoms of psychiatric disorders, and diminishing response to levodopa or excessive dyskinesia.

Dyskinesia

Dyskinesia, when troublesome or debilitating, can usually be managed with amantadine and clozapine. The carbidopa-levodopa intestinal gel also results in overall lower frequency of dyskinesia. Combinations of different medications may be required to control dyskinesia in some patients. The overall goal should be to ensure that the patient experiences maximizing on- time, minimizing troublesome dyskinesia and minimizing off-time. A diary or log book can be helpful to monitor response and to re-evaluate efficacy of medications if needed.82,83,143-148

Motor Fluctuations with Dyskinesia

Patients with motor fluctuations and dyskinesia present a special difficulty because decreasing dopaminergic therapy may increase the ‘off’ times and increasing dopaminergic therapy may exacerbate peak-dose dyskinesia. The approach is to give smaller doses of levodopa more frequently, keeping the off-time in mind to help judge the frequency of the lower dosages. In particularly difficult control situations, liquid levodopa may be used to more precisely titrate the dose.

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Carbidopa-levodopa along with a COMTI can be used to maintain levodopa levels. The COMTI tolcapone can cause hepatotoxicity. This means that patients treated with tolcapone will require regular liver function tests. Entacapone does not cause hepatotoxicity and may be a better choice for some patients. A combination of carbidopa-levodopa-entacapone has been approved for use in PD patients.

Dopamine agonists can be used in combination with levodopa, but may increase the severity of the disease while delaying dyskinesias and motor fluctuations. If dopamine agonists are used, the dose of the levodopa should be decreased accordingly.

Amantadine, an antiviral drug, may also be used to treat dyskinesia. Recently, the results of the AMANDYSK trial were published, indicating that amantadine was effective in reducing dyskinesia over a period of several years in patients with levodopa induced dyskinesia. The AMANDYSK trial was a 3 month, multicenter trial designed to assess long-term efficacy of chronic treatment with amantadine in patients with PD and levodopa-induced dyskinesia (LID). The trial also provided evidence (Class II) that withdrawal of amantadine significantly exacerbated levodopa-induced dyskinesia within a median 7-day period. In addition, the use of amantadine was effective in improving apathy and fatigue in PD patients.

In another recent clinical study (a randomized, double-blind, placebo- controlled, parallel-group study) of a long-acting, extended release form of amantadine, ADS-5102 found that 340 mg of ADS-5102 reduced dyskinesia by 27% as measured by the Unified Dyskinesia Rating Scale (UDysRS). ADW-5102 also increased ‘on’ time without dyskinesia at both 260 mg and at 340 mg. Adverse reactions however, were a concern with up to 90% of

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Nausea

Nausea can often be minimized by taking medication with food. Adding an additional dose of a dopa decarboxylase inhibitor such as carbidopa or benserazide can prevent peripheral conversion to dopamine and can reduce levodopa-induced nausea. Metoclopramide, prochlorperazine and promethazine should be avoided because these medications can worsen parkinsonian symptoms.

It should be noted here that high protein meals can limit or slow the absorption of levodopa. Protein should be limited to meals that are consumed between dosing, and not when a patient is administered levodopa. A recent study indicated that 5.9% of patients on levodopa and 12.4% of patients with motor fluctuations while on levodopa could correlate their motor fluctuations, as characterized by dose failures (longer time to be effective or earlier wearing off), sudden, painful or behavioral wearing-off periods, gait freezing, nausea, hallucinations, orthostatic hypotension, and dyskinesias) with protein intake. These patients had predominantly been diagnosed at a younger age and had family history of PD. Another recent study recommended managing protein intake and energy intake in patients, taking into consideration digestive-related constipation and therefore ensuring a high fiber diet.

Choice Of Therapy For Dyskinesia In Parkinson’s Disease

As discussed above, in advanced PD, there are three, device-aided therapies that are currently available to treat motor fluctuations or dyskinesia: 1) continuous subcutaneous apomorphine infusion, 2) continuous 45 ce4less.com ce4less.com ce4less.com ce4less.com ce4less.com ce4less.com duodenal/jejunal carbidopa/levodopa pump infusion (DLI), and 3) deep brain stimulation. It can be difficult to choose between these three therapies. They have significantly different adverse effect profiles, degree of invasiveness and supportive care. In determining whether any device-aided therapy is preferable over another in managing target motor symptoms of PD, the severity of off-period symptoms are evaluated.81,84-90,104,105

In general, the evidence supports the effectiveness of deep brain stimulation (DBS) on motor fluctuations and dyskinesia compared to continuous subcutaneous apomorphine infusion or DLI. Deep brain stimulation consistently proved to be more effective at reducing off-period motor symptoms and increasing on-time without dyskinesia. Deep brain stimulation may be effective to treat tremor in cases where tremor is refractory, i.e., unresponsive to levodopa or other oral dopaminergic drugs.

Apomorphine may be effective controlling daytime motor fluctuations and it has a variable effect on dyskinesia but existing evidence is too weak on these points. Twenty-four-hour dopaminergic infusion therapy has safety concerns and there is uncertainty surrounding dose adjustments that may be required during the night. Off-time reduction with DLI is limited to the daytime but some nighttime effects have been reported; additionally, it appears that DLI is effect for treating dyskinesia but more studies are needed.

Patient-related Factors

In determining whether DBS, DLI or continuous subcutaneous apomorphine infusion therapy is the preferred therapy for a patient, the age of the patient, onset of the disease, and the patient’s cognitive and neuropsychiatric status are important factors.

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Age and Duration of Disease

Deep brain stimulation in a younger age has been reported to predict a more favorable response with respect to motor and improvement in quality of life. Studies comparing older patients (>70 years) to younger patients evaluated on-time without dyskinesia and off-period UPDRS motor scores. There was a higher risk of non-serious adverse events (AEs) in older patients, but no difference between older and younger patients in the rate or type of serious AEs. This addressed the concern of some clinicians that the progression of motor signs and emerging dementia may counteract improved activities of daily living after DBS specifically in older patients.

The chance for DBS to be effective when fluctuations and dyskinesia emerge to adversely impact qualify of life in younger patients have also been addressed. The reliable long-term results have been observed in patients with PD with an average of 15 years before surgery; and, evolving dementia or gait disturbance risk appears higher with a longer disease duration.

Apomorphine was effective in older patients (up to 85 years) with a long disease duration. No relationship between age and disease duration on the outcome of treatment was observed. No studies stratified AEs by age.

Duodenal levodopa infusion (DLI) can be effective in patients of all ages and with a long disease duration. DLI appears an effective last-line therapy for PD motor complications, with suggestions to prefer it over other device- assisted therapies in older, frail patients because of better tolerability.

Researchers have concluded that while DBS of the subthalamic nucleus can confer improvements in motor symptoms in older patients (>70 years), it may provide greater benefits in younger patients regarding activity of daily living (ADL) and quality of life (QoL), with a seemingly lower risk of AEs.

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DBS should not be considered a treatment of last resort as better results might be obtained in younger patients with a shorter duration of motor complications. The durability of the treatment effect, which can be counteracted by the evolution of axial motor symptoms and cognitive decline, should be discussed with older surgical candidates.

The efficacy of apomorphine on motor symptoms does not seem to depend on age or disease duration, but there are insufficient and contradictory data to conclude on safety in older patients, in particular the risk of psychosis and confusional states. Additionally, there is no evidence of an age-related decline with DLI, which seems to be well tolerated, even in older patients with very advanced PD including some cognitive decline.

Cognitive and Neuropsychiatric Status

It is recommended that neuropsychiatric assessment is carried out before any device-aided therapy and that patients with previous psychiatric history receive post-treatment neuropsychiatric surveillance, especially in cases where the patient has an ongoing psychosis or impulse control disorders. In addition, a clinician will want to review a patient’s general cognitive status by answering the questions raised below.

Cognitive Status:

What effect does each therapy have on the patient’s cognitive status? Can this be used to recommend a treatment?

The data is limited so there is no definitive way to answer these questions; however, as mentioned above, one of the indications for DBS is the absence of symptoms of psychiatric disorders. As such, in those on a clinical course suggestive of imminent cognitive decline there should be careful monitoring.

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Data on the cognitive safety of apomorphine or DLI is inconclusive. A patient receiving apomorphine or DLI therapy may experience an acute, confusional state, but these therapies should not impact dementia in PD. Neuropsychiatric Status:

Does the patient’s neuropsychiatric status before treatment affect outcomes? Can any therapy be recommended in patients with pre-existing neuropsychiatric problems?

Subthalamic nucleus-deep brain stimulation usually led to an improvement in depressive mood ratings, apathy and anxiety but some patients experienced an increase in the risk of aggravation. Suicide risk increased within the first year of the procedure, with a return to baseline after three years.

Based on limited evidence, apomorphine may improve a patient’s mood and anxiety but it is associated with a risk of psychosis, confusion and disinhibited behavior. Twenty-four-hour infusion therapy has safety concerns because of the risk of exacerbating psychiatric complications.

With DLI neuropsychiatric adverse events were limited. Improvements were observed with some psychiatric symptoms, such as depression, anxiety, delusions, hallucinations, in patients with mild-to-moderate cognitive impairment and previous psychosis. This may have been due to the change from oral antiparkinsonian polypharmacy to levodopa monotherapy.

Medical Comorbidities

A medical comorbidity may preclude a treatment. In DBS the medical contraindications are awake stereotactic neurosurgery, severe brain atrophy or lesions that may interfere with the procedure. Anticoagulation or cardiac devices are not strict contraindications but complicate surgery. 49 ce4less.com ce4less.com ce4less.com ce4less.com ce4less.com ce4less.com

For patients with diabetes mellitus who have wound healing issues, cellulitis or skin problems, apomorphine therapy may be problematic. Previous abdominal surgery may interfere with DLI since it may not allow the placing of a gastrojejunostomy, in which case it would be contraindicated. Inflammatory demyelinating polyneuropathy is a possible severe adverse event but the impact on preexisting polyneuropathy has not been established. The weight of the pump may be a relative contraindication or burden in frail patients. Patients should be advised about their individual risks and counseled as to whether they outweigh the expected benefits of any device-aided therapy.

Other Factors and Quality of Life

A clinician should be aware of the impact a therapy may have on a patient’s quality of life. This may include an analysis of non-motor symptoms, risk of dysarthia, or gait and balance problems. Because studies of non-motor symptoms are limited, non-motor symptoms should not be a decisive reason for recommending one therapy over another therapy. A clinician will want to review a patients sleep, status or loss of energy as a case-by-case basis. No significant data exists on whether one of these therapies increases the risk of dysarthria but clinical observations suggest this is not a factor.

Falls or gait disturbance have been reported as an adverse evdent in STN– DBS but it is unclear whether this is an effect of the procedure or the medications following surgery. Paradoxically, the increase in falls or gait distrubances may be a result of the patient’s increased mobility after the procedure, especially in patients with preexisting postural instability. In one study, apomorphine has been associated with a significant improvement in gait imbalance. With DLI, almost two-thirds of patients

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Psychiatric Comorbidities

Dementia, depression, hallucinations, anxiety, cognitive impairment, sleep disturbances, and impulse control disorders are all associated with PD, significantly adding to the disease burden. Many of these disorders are directly due to the pathological changes within the brain, but are also due to adverse effects of the standard dopaminergic therapies.

Cognitive Impairment

Mild cognitive impairment may be evident even before a diagnosis of PD or may develop as the disease progresses. Approximately 35% of individuals present with cognitive impairment and signs of cognitive impairment will appear in about 50% of all patients within 5 years of diagnosis, depending on which assessment tool is used. The most common type of mild cognitive impairment seen in PD is non-amnestic, single-domain impairment. This type affects domains of executive function, psychomotor speed, visuospatial processing or attention. Multiple cognitive domains can also be affected though language is usually spared. The presence of mild cognitive impairment is a good predictor of dementia, though it is not clear if amnestic or non-amnestic cognitive impairment is a better predictor. If patients with Parkinson-like symptoms develop dementia within a year of diagnosis, a new diagnosis of dementia with Lewy bodies is made.

Inclusion Criteria

• Diagnosis of Parkinson’s disease, in the context of established PD, in cognitive ability reported by either the patient or informant, or observed by the clinician. 51 ce4less.com ce4less.com ce4less.com ce4less.com ce4less.com ce4less.com

• Cognitive deficits on either formal neuropsychological testing or a scale of global cognitive abilities. • Cognitive deficits are not sufficient to interfere significantly with functional independence, although subtle difficulties on complex functional tasks may be present.

Exclusion Criteria • Diagnosis of PD dementia based on MDS Task Force proposed criteria. • Other primary explanations for cognitive impairment (i.e., delirium, stroke, major depression, metabolic abnormalities, adverse effects of medication, or head trauma). • Other PD-associated comorbid conditions (i.e., motor impairment or severe anxiety, depression, excessive daytime sleepiness, or psychosis) that, in the opinion of the clinician, significantly influence cognitive testing.

Specific Guidelines for PD-MCI Level I and Level II Categories

Level I (abbreviated assessment) • Impairment on a scale of global cognitive abilities validated for use in PD, or • Impairment on at least two tests, when a limited battery of neuropsychological tests is performed (i.e., the battery includes less than two tests within each of the five cognitive domains, or less than five cognitive domains are assessed)

Level II (comprehensive assessment) • Neuropsychological testing that includes two tests within each of the five cognitive domains (i.e., attention and working memory, executive, language, memory, and visuospatial) • Impairment on at least two neuropsychological tests, represented by either two impaired tests in one cognitive domain or one impaired test in two different cognitive domains • Significant decline from estimated premorbid levels

Subtype classification for PD-MCI (optional, requires two tests for each of the five cognitive domains assessed and is strongly suggested for research purposes) • PD-MCI single-domain—abnormalities on two tests within a single cognitive domain (specify the domain), with other domains unimpaired or • PD-MCI multiple-domain—abnormalities on at least one test in two or more cognitive domains (specify the domains)

Impairment on neuropsychological tests may be demonstrated by: • Performance approximately 1 to 2 SDs below appropriate norms or • Significant decline demonstrated on serial cognitive testing or significant decline from estimated premorbid levels.

The Movement Disorder Society has provided diagnostic criteria for mild cognitive impairment in Parkinson’s disease (PD-MCI). Tests for global cognition include the MoCA (Montreal Cognitive Assessment), the PD-CRS (Parkinson’s Disease-Cognitive Rating scale), the SCOPA-COG (Scales for

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Outcomes of Parkinson’s disease–Cognition) and the MDRS (Mattis Dementia Rating Scale). The National Adult Reading Test (NART) and the Wechsler Test of Adult Reading (WTAR) can be used to assess premorbid intelligence in patients with dementia. Dementia In Parkinson’s Disease

There is evidence that the dementia in Parkinson’s disease (PDD) is a progression of the earlier mild cognitive impairment, but this is not established. The Mini-Mental State Examination (MMSE or Folstein test) may be used to assess for dementia. It is a quick, maximum 30-point test designed to test for dementia.1,12,58-63

Table 4: The MMSE

Maximum Patient’s Question Score Score 5 “What is the year? Season? Date? Day? Month?”

5 “Where are we now? State? County? Town/city? Hospital? Floor?”

3 The examiner names three unrelated objects clearly and slowly, then the instructor asks the patient to name all three of them. The patient’s response is used for scoring. The examiner repeats them until patient learns all of them, if possible.

5 “I would like you to count backward from 100 by sevens.” (93, 86, 79, 72, 65, …) Alternative: “Spell WORLD backwards.” (D-L-R-O-W)

3 “Earlier I told you the names of three things. Can you tell me what those were?”

2 Show the patient two simple objects, such as a wristwatch and a pencil, and ask the patient to name them.

1 “Repeat the phrase: ‘No ifs, ands, or buts.’”

3 “Take the paper in your right hand, fold it in half, and put it on the floor.” (The examiner gives the patient a piece of blank paper).

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1 “Please read this and do what it says.” (Written instruction is “Close your eyes.”)

1 “Make up and write a sentence about anything.” (This sentence must contain a noun and a verb).

1 “Please copy this picture.” (The examiner gives the patient a blank piece of paper and asks him/her to draw the symbol below. All 10 angles must be present and two must intersect.)

30 TOTAL

Interpretation A score less than 24 is abnormal. Scores <21 indicate an increased risk of dementia, while score >25 indicate a decreased risk of dementia. The score interpretation can vary based on educational level as well.

A score <21 is considered abnormal for an individual with an 8th grade education; a sore of <23 is considered abnormal for an individual with an high school education; a score <24 is considered abnormal for an individual with a college education.

Severity 24-30 No cognitive impairment

18-23 Mild cognitive impairment

0-17 Severe cognitive impairment

Score Degree of Psychometric Assessment Day-to-Day Functioning Impairment 25-30 Significance If clinical signs of cognitive May have clinically is impairment are present, formal significant but mild deficits. questionable assessment of cognition may be Likely to affect only most valuable. demanding activities of daily living. 20-25 Mild Formal assessment may be Significant effect. May helpful to better determine require some supervision, pattern and extent of deficits. support and assistance.

10-20 Moderate Formal assessment may be Clear impairment. May helpful if there are specific require 24-hour clinical indications. supervision.

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with ADL.

In addition, the MDS has generated clinical diagnostic criteria for dementia associated with PD, including features of dementia associated with PD. The Queen Square Brain Bank Criteria for the diagnosis of Parkinson’s disease is outlined below.

Core features 1. Diagnosis of Parkinson’s disease according to Queen Square Brain Bank criteria 2. A dementia syndrome with insidious onset and slow progression, developing within the context of established Parkinson’s disease and diagnosed by history, clinical, and mental examination, defined as: • Impairment in more than one cognitive domain • Representing a decline from premorbid level • Deficits severe enough to impair daily life (social, occupational, or personal care), independent of the impairment ascribable to motor or autonomic symptoms

Associated Clinical Features Cognitive features: • Attention: Impaired. Impairment in spontaneous and focused attention, poor performance in attentional tasks; performance may fluctuate during the day and from day to day • Executive functions: Impaired. Impairment in tasks requiring initiation, planning, concept formation, rule finding, set shifting or set maintenance; impaired mental speed (bradyphrenia) • Visuo-spatial functions: Impaired. Impairment in tasks requiring visual-spatial orientation, perception, or construction • Memory: Impaired. Impairment in free recall of recent events or in tasks requiring learning new material, memory usually improves with cueing, recognition is usually better than free recall • Language: Core functions largely preserved. Word finding difficulties and impaired comprehension of complex sentences may be present

Behavioral features: • Apathy: decreased spontaneity; loss of motivation, interest, and effortful behavior • Changes in personality and mood including depressive features and anxiety • Hallucinations: mostly visual, usually complex, formed visions of people, animals or objects • Delusions: usually paranoid, such as infidelity, or phantom boarder (unwelcome guests living in the home) delusions • Excessive daytime sleepiness

Features which do not exclude PD-D, but make the diagnosis uncertain

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• Co-existence of any other abnormality which may by itself cause cognitive impairment, but judged not to be the cause of dementia, i.e., presence of relevant vascular disease in imaging • Time interval between the development of motor and cognitive symptoms not known

Features suggesting other conditions or diseases as cause of mental impairment, which, when present make it impossible to reliably diagnose PD-D • Cognitive and behavioral symptoms appearing solely in the context of other conditions such as: Acute confusion due to - Systemic diseases or abnormalities - Drug intoxication - Major Depression according to DSM V • Features compatible with “Probable Vascular dementia” criteria according to NINDS- AIREN (dementia in the context of cerebrovascular disease as indicated by focal signs in neurological exam such as hemiparesis, sensory deficits, and evidence of relevant cerebrovascular disease by brain imaging AND a relationship between the two as indicated by the presence of one or more of the following: onset of dementia within 3 months after a recognized stroke, abrupt deterioration in cognitive functions, and fluctuating, stepwise progression of cognitive deficits).

Mild cognitive impairment and cognitive impairment progressing to dementia can present with a wide variety of deficits including memory deficits, visuospatial dysfunction and executive functions. Patients can present with an amnestic, dysexecutive or mixed profile. These may be assessed using a range of cognitive tests. The Wechsler Adult Intelligence Scale (WAIS-IV) measures cognitive ability with 10 subtests and 5 supplemental subtests focusing on verbal comprehension, perceptual reasoning, working memory, and processing speed domains. It may be administered with paper and pencil or online.87-89

The Trail Making Test (TMT) is a test of visual attention and the ability to switch tasks. There are two parts to the TMT; in the first part the patient connects numbered targets in numerical order. In the second part of the test, the patient connects lettered and numbered targets. The Stroop color and word test can differentiate between normal individuals, non-brain- damaged psychiatric patients and brain-damaged patients. It is based on the

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“Stroop Effect” - that individuals can read words much faster than they can identify and name colors. The test measures cognitive flexibility and resistance to outside stressors. This is a timed test where various words are printed in different colors. The patient is asked to name the colors, not the words.

The Wisconsin Card Sorting Test assesses the ability to show evidence of flexibility and abstract thinking. It is believed to test executive function. There are 128 stimulus cards with three parameters - color, form and number. However, no ‘rules’ are given regarding how to sort. They could be sorted on the basis of color, form or number and this can vary during the test so that the patient must vary their approach to the sorting task. The Nelson Modification simplifies the test for the elderly, reducing the number of cards to be sorted.

The Tower of London test assesses executive functions with the specific goal of detecting planning deficits, impulse control, attention allocation, rule- governed behavior and self-monitoring. It is related to the classic Tower of Hanoi puzzle and consists of tower boards with pegs and beads of various colors with which the patient performs a number of problem-solving tasks. Each test begins with a demonstration, followed by two practice times. The test has 10 parts of increasing difficulty.

The Stockings of Cambridge (SOC) test is a spatial planning test. Patients use problem solving strategies to match two sets of stimuli - balls hung in a stocking. The patient is asked to match the lower set with the upper set and is assessed based on the number of correct solutions and the speed of the response. Various verbal fluency tests are available, including the Controlled Oral Word Association Test (COWAT).

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The Clock Drawing Test is used as a measure of spatial dysfunction, visuo- constructive abilities and executive functions. A clock is drawn and the patient is asked to fill in the numbers and then fill in a number of different times. Also, the Boston naming test measures word retrieval using 60 drawings with different levels of difficulty. The Graded Naming Test also uses images varying in difficulty.

There are a variety of tests measuring memory functions including the Rey’s Auditory Verbal Learning test. The Rey’s Auditory Verbal Learning test (RAVLT) provides a list of 15 unrelated words over 5 different trials followed by another list of 15 unrelated words. The patient is asked to repeat the original list after 15 and 30 minutes. The California Verbal Learning Test (CVLT) is similar to the RAVLT.

Table 5: Names of Common Tests for Assessment of Different Cognitive Domains Cognitive Domain Test Name Time Required for Tested Testing Attention and • Wechsler Adult Intelligence Scale (WAIS-IV) 5-10 minutes, Working memory • Trail Making Test (TMT) depending on the • Stroop color and word test test

Executive function • Wisconsin Card Sorting Test (CST), ~ 15 minutes, • Nelson’s Modified CST depending on the • Tower of London Test-Drexel University test (TOLDX) • Stockings of Cambridge (SOC) test • Verbal fluency tests • Clock Drawing Test

Language • WAIS-IV ~ 15 minutes, • Boston Naming Test depending on the • Graded Naming Test test

Memory • Rey’s Auditory Verbal Learning Test ~ 15 minutes, • California Verbal Learning Test depending on the • Hopkins Verbal Learning Test test • Selective Reminding Test • WAIS-IV: Logical Memory subtest • Brief Visuospatial Memory Test

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Visuospatial • Benton’s Judgment of Line Orientation 5-10 minutes function • Hooper Visual Organization Test

Pharmacologic Treatment For Neuropsychiatric Symptoms

Neuropsychiatric symptoms add considerably to the burden of Parkinson’s disease. Mood disorders such as depression and anxiety can predate motor symptoms. Other symptoms including mild cognitive impairment, dementia, hallucinations, paranoid delusions, impulse control disorders, addictive disorders, depression and anxiety. These conditions may be adverse effects of dopaminergic treatment or they may be directly related to the pathological changes associated with PD. There have been a number of important placebo controlled randomized double-blinded studies examining the use of medications in treating neuropsychiatric comorbidities.21,22,62

Neuropsychiatric Comorbidities

Mild Cognitive Impairment

• Rasagiline (1mg) improved compositional z-attention scores, but did not significantly improve other domains.

Dementia Associated with Parkinson’s disease

• Donepezil (10 mg) improved the Clinicians Interview Based Impression of Change with Caregiver input (CIBIC) significantly while 5 mg did not show improvement. • Rivastigmine (9-12 mg) improved the cognitive subscale of the Alzheimer Disease Assessment Scale (ADAS-Cog) and the Alzheimer Disease Co-

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operative Study Clinicians Global Impression of Change (ADCS-CGIC) scoring. • Memantine (5-20 mg) was effective in the Dementia with Lewy Body test group.

Psychotic Symptoms

• Clozapine (6.25-50 mg) was studied by two different groups. In both studies, there was significant improvement of symptoms over placebo with no worsening of motor symptoms. Response was assessed by the Clinical Global Impression Scale (CGIS) and the Unified Parkinson’s Disease Rating Scale (UPDRS). • Olanzapine (2.5-15mg) and Quetiapine (variable dosing) were not significantly effective over placebo.

For symptoms of depression, a recent review and meta-analysis concluded that selective serotonin reuptake inhibitors (SSRIs) and cognitive behavioral therapy (CBT) were effective as treatment approaches. Other classes of anti- depressive agents were not as effective as the SSRIs. In addition, however, the authors noted that tricyclic antidepressants (TCAs) provided more rapid symptomatic relief and were effective in improving sleep.

Tricyclic antidepressants should be used cautiously in elderly patients. Tricyclic antidepressants may exacerbate motor symptoms and worsen neuropsychiatric symptoms including cognitive impairment, visual hallucinations, delusional thought disorders, impulse control disorders as well as exacerbating autonomic symptoms.

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Dopamine agonists did not demonstrate efficacy in this meta-analysis and the authors concluded that there was insufficient evidence to recommend the use of dopamine agonists to treat depression.

Non-Pharmacological Therapies In Parkinson’s Disease

Non-pharmacological therapies have proven useful in treating PD. These include cognitive behavior therapy, which has shown a statistically significant effect, cognitive training to improve cognitive functions, repetitive transcranial magnetic stimulation (rTMS), and neuroprotective therapy.93,94,101,109-111,114

Cognitive Behavioral Therapy

Cognitive behavioral therapy (CBT) is a short-term and specifically goal- oriented form of psychotherapy. Combining classic psychotherapy and behavioral therapy. Cognitive behavioral therapy attempts to change patterns of thinking or behavior at the core of a mood disorder in order to change an individual’s response. A recent systematic review examining CBT in chronic neurological conditions found that CBT holds promise in the treatment of PD (and other chronic neurological disorders) but that treatment protocols and outcome measures should be adapted for this population.

Cognitive Training

Cognitive training recognizes the plasticity of the human brain and uses guided practice for various sets of tasks designed to improve memory, attention, problem-solving skills, decision-making skills, reasoning and other domains. Typically, cognitive training uses repetitive exercises, delivered in person or by using specialized software (online and offline) to improve single

61 ce4less.com ce4less.com ce4less.com ce4less.com ce4less.com ce4less.com or multiple domains. A systematic review and meta-analysis was published in 2015 which examined the current literature on cognitive training in PD. The authors concluded that cognitive training represented a safe and modestly effective approach for patients with mild to moderate PD. Larger controlled trials involving cognitive training as secondary prevention of cognitive decline would be needed to support future recommendations for clinicians in the planning of patient care.

Repetitive Transcranial Magnetic Stimulation

Repetitive transcranial magnetic stimulation (rTMS) is a non-invasive neuromodulation technique. The rTMS delivers low-frequency magnetic pulses in iterations within a short period of time to specific areas of the brain. It is a non-invasive tool which is relatively painless. The rTMS is used to study brain-behavior relationships, various cognitive functions and as a therapeutic approach in several neuropsychiatric disorders, including depression, anxiety, schizophrenia, mania, epilepsy and substance use.

Immediate effects of rTMS can include jerky movements, perceptions of light flashes and other generally mild effects. Different frequencies of magnetic stimulation can have different biologic effects. Low frequency rTMS can result in the inhibition of cell-to-cell communications whereas high frequency rTMS can stimulate and improve cell-to-cell communications. In addition, long-term effects include changes in neurotransmitter levels, signaling pathways and gene expression.

In PD, rTMS has been shown that application at the primary motor cortex and at the prefrontal cortex (0.2 Hz-5 Hz) with a variable intensity can induce improvement in symptoms of depression, anxiety, motor functions, gait, and bradykinesia. A recent review of the literature concluded that rTMS at the primary motor cortex can improve motor signs. In addition, a meta- 62 ce4less.com ce4less.com ce4less.com ce4less.com ce4less.com ce4less.com analysis of randomized controlled clinical trials using rTMS to treat depression in PD was recently published. The authors concluded that rTMS was similar to anti-depressants (selective serotonin reuptake inhibitors (SSRIs)) as regarding the unified PD rating scale (UPDRS), ADL score, and UPDRS motor score as compared with sham-rTMS or SSRIs.

Neuroprotective Therapy

Neuroprotective therapy can be thought of as a treatment that decreases the loss of dopaminergic neurons. In PD, the possible improvement of mitochondrial function or increasing degradation of defective mitochondria are addressed through the use of kinase inhibitors, and calcium channel blockers. Some of the targets that are currently being investigated include: • LLRK2 kinase inhibitors for those that carry the LRRK2 mutation • Glucocerebrosidase modulators for those that carry GBA mutations • Pro-mitochondrial/antioxidant agents can reduce oxidative stress, i.e.,: - PPAR-γ activators - Anti-inflammatory agents - Antioxidants (i.e., creatine, polyphenols, Vitamin E, CoQ10, idebenone (synthetic analog of COQ10) - Rasagiline: The ADAGIO (Attenuation of Disease progression with Azilect Given Once-daily) and TEMPO (Rasagiline in Early Monotherapy for Parkinson's Disease Outpatients) studies using rasagiline in early PD did not provide strong evidence for neuroprotective activity of rasagiline - Agents that increase mitochondrial biogenesis (i.e., GLP-1-like peptide exendin-4 (EX-4)) - Treatments to enhance autophagy-mitophagy • Agents that can positively reverse protein disaggregation • Calcium channel blockers designed to stabilize mitochondrial membranes

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- Selective Ca(v) 1-3 channel inhibitors • Agents that can affect protein folding - Heat-shock proteins to act in re-folding misfolded proteins and to act as chaperones, transferring to proteasomes for digestion - Agents that can increase the clearance of misfolded proteins

• Trophic factors activating protective signals - GNDF family of trophic factors - Neurturin • Other - Ubiquinone - PYM50028 (Cogane)

Mitochondrial-directed anti-oxidant therapies are an interesting focus because antioxidant therapies, listed above, can act in a diffuse way, targeting mitochondria specifically is an area of research. Also, agents being investigated include 1) Mitoquinone, consisting of a triphenylphosphonium (TPP)cation bound to CoQ1, 2) Mitotocopherol and MitoTEMPO, which consist of a TPP cation bound to vitamin E, and 3) Szeto-Schiller peptides, which include cationic peptides (aromatic) that are trophic for the inner mitochondrial membrane. Dimethyltyrosine residues in the peptides scavenge free radicals.

Deep Brain Stimulation

Deep brain stimulation (DBS) has been studied relative to its ability to improve sleep dysfucntion in advanced PD patients. Some authors identify improvement in quality of sleep, an increase in total sleep time, time spent in REM, and slow wave sleep as measured by polysomnography and the Parkinson disease subjective sleep scale (PDSS). These improvements were

64 ce4less.com ce4less.com ce4less.com ce4less.com ce4less.com ce4less.com noted when the simulation was off and may be due to lesions in the subthalamic nucleus.

Questions that remain unanswered regarding DBS include: • Unilateral versus bilateral leads, simultaneously implanted • Symptoms not currently addressed by DBS, such as gait freezing, possibly sleep dysfunction • DBS being used earlier in the disease process (a recent study indicated that patients treated within the first 4 years after PD diagnosis were 2 to 5 times less likely to experience clinically significant worsening of symptoms)

Deep brain stimulation has complications and safety issues. Surgical complications include:

• Infection (4%) • Intracranial hemorrhage (4.4%); permanent damage or deficit occurs in 1% of these patients • Migration of leads (2.4%) • Lead breakage (3%) • Seizures (3.2%)

Other adverse effects include: • Dysarthria • Dysphagia • Excessive salivation • Blepharospasms • Weight gain • Cognitive changes • Delirium 65 ce4less.com ce4less.com ce4less.com ce4less.com ce4less.com ce4less.com

• Hallucination • DBS failure

Neuroablative Therapy

Targeted destruction of specific areas has been used to treat Parkinson’s disease, though these have largely been replaced with deep brain stimulation. Ablation involves the creation of a lesion using essentially cauterization techniques. DBS is preferred because it is reversible, can be controlled by programming and can be safely performed bilaterally.

Alternative And Complementary Therapies For PD

Alternative and complementary approaches to PD include herbal treatments, acupuncture, acupressure, nutraceuticals and supplements and mind-body interventions such as Tai chi, Qigong, meditation and yoga. In addition, traditional medical systems such as Traditional Chinese Medicine (TCM), Ayurvedic medicine and other traditional systems. These approaches focus on individuality over typology, a holistic approach to wellness, and an emphasis on the importance of patient empowerment in the healing process.114-119,121,123

Tai chi and Qigong

In the largest study to date, Li, et al., demonstrated that patients who had been randomized into a Tai chi group over one that utilized conventional resistance training performed significantly better with measures of postural stability and had fewer falls. Also, authors of a recent systematic review and meta-analysis concluded that performing classical Qigong (and Tai chi) leads to clinically meaningful improvements in multiple domains of motor function and fall risk and that utilizing Qigong and Tai chi can lead to improvement in

66 ce4less.com ce4less.com ce4less.com ce4less.com ce4less.com ce4less.com mood and overall quality of life. Other studies have indicated that Qigong may improve sleep quality and gait performance.

Acupuncture and Moxibustion

Both acupuncture and moxibustion can be difficult to properly control. In one well-controlled but small study, there were no significant effects in either motor or non-motor outcomes. A recent review of clinical studies using acupuncture concluded that while the effectiveness of acupuncture to treat PD is not clear in research studies, the therapeutic potential of acupuncture appears hopeful. More studies, either comparative effectiveness research or high-quality placebo-controlled clinical studies are warranted.

Massage and Other Manual Therapies

There is a lack of literature on massage and manual therapies and the effect on PD, though there is a rationale for the use of these physical approaches.

Botanical Therapies

Many of the botanical approaches address oxidative stress. Some of the botanical approaches that have been used, primarily as adjuncts are highlighted here.

• Acanthopanax senticosus has been shown to be effective and protective against oxidative stress in animal models. One of the “active” principles in A. senticosus extracts is sesamin which has been shown to induce superoxide dismutase, tyrosine hydroxylase, inducible nitric oxide synthase and IL-6 expression in oxidative stress induced by 1-methyl-4- phenylpyridine (MPP) in animal models.

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• Astragalus membranaceus prevents MPP-induced cell death. Astragaloside IV appears to be active in this regard. Astragaloside IV also prevents dopaminergic cell death induced by 6-OHDA in a dose- dependent manner. • Camellia sinensis is the tea that produces green tea. Green tea is associated with a decreased risk of PD and attenuates 6-OHDA-induced apoptosis. • Ergot alkaloids have broad effects including antiserotonin, dopaminomimetic, and antiadrenergic activities and can act as partial agonists or antagonists at serotonergic, dopaminergic, adrenergic, and tryptaminergic receptors. Pergolide, bromocriptine and lisuride are orally active synthetic ergot alkaloids that have shown some promise in the treatment of PD. • Ginseng is used to describe a family of plants in the genus Panax. The different plants that the term encompasses including Korean or Asian ginseng (Panax ginseng), American ginseng (Panax quinquefolius), and Siberian ginseng (Eleutherococcus senticosus) have distinct medicinal profiles. Panax ginseng has been the most studied and has been shown to stimulate the regeneration of neurons.

Other botanical medicines that may have neuroprotective and protect against chemically induced apoptosis include Rhodiola rosea/crenulate, Polygonum cuspidatum spp, slavia spp, Polygala spp, and Hypericum perforatum (St. John’s wort). Cannabis or medical marijuana has been reviewed and according to a recent systematic review from the Guideline Development Subcommittee of the American Academy of Neurology, oral cannabis extract (OCE) is not significantly effective for levodopa-induced dyskinesia in PD patients. However, a recent article concerning self-reported efficacy of cannabis indicated that 78% of cannabis users reported general

68 ce4less.com ce4less.com ce4less.com ce4less.com ce4less.com ce4less.com improvement, 55% reported improvement in mood, and 55% reported relief of sleep dysfunction.

Dietary Considerations

Some nutrients or dietary components have been implicated with an increased risk of PD, though none have been definitively correlated with an increased risk. Dairy consumption may increase the risk of PD in both men and women. It is unclear if dairy products or pesticides and/or polychlorinated biphenyls play a role in this association as well or if they may be independently associated with a higher risk.

Phytochemicals, particularly phyto-antioxidants, have been studied as potential treatments for PD with few positive results, although continuing research indicates that phyto-antioxidants may be more useful in the prevention of PD than in the treatment of PD.

Carotenoid intake has been associated with a decreased risk of PD and protection against animal models of neurotoxicity, but while there is epidemiological evidence of neuroprotection, given the complexities of PD, it is less clear that increasing carotenoid intake would be protective or preventative. Similarly, omega-3 fatty acids such as EPA (Eicosapentaenoic acid) or DHA (Docosahexaenoic acid) appear to confer some degree of neuroprotection, there are few clinical studies addressing the use of omega- 3 fatty acids in the treatment of PD. Omega-3 fatty acids have been shown to be effective neuroprotectants in some animal models of PD, and there is a theoretical basis for targeting therapeutic interventions and establishing more rigorous dietary recommendations.

A recent systematic review addressed nutrition and PD. All studies had more than 200 participants with all having detailed methods of nutritional

69 ce4less.com ce4less.com ce4less.com ce4less.com ce4less.com ce4less.com histories. The systematic review indicated that liquid whole milk was identified as a specific risk factor for PD. Coffee and black teas (but not green teas) were determined to be protective. Foods of the solenaceae family (the nightshades such as tomatoes, peppers, and eggplant) were protective - possibly because of the nicotine content. The study also found that individuals who followed the Mediterranean diet, which includes high vegetable, fruit and fish content along with whole grains, primary use of olive oil, may be protective against PD. Interestingly, dietary cholesterol was found to be protective in men only; dietary cholesterol did not confer any significant protection for women. Conversely, mono-unsaturated fatty acid (MUFA) was found to be protective for women, with no significant effects on men.

Studies have indicated that adherence to a Mediterranean diet can reduce the risk of PD. Given the incidence of constipation, a high fiber diet, such as in the Mediterranean diet, may prove to be beneficial for PD. Also, a low- protein diet, or at least a dietary approach which distributes protein intake throughout the day, may be beneficial in PD because a high protein intake may interfere with levodopa absorption. The 2015 U.S., Dietary Guidelines addressed diet and the risk of neurodegenerative disorders such as PD now suggest that research on dietary patterns and neurodegenerative disease risk has grown, which includes high-quality observational studies (comprising most of the evidence). While there is no consensus on dietary considerations in prevention or treatment of PD, there are important dietary guidelines in supporting patients with PD, particularly to improve quality of life.

A recent publication looked at nutritional status and quality of life in patients with PD. The authors concluded that individuals suffering from malnutrition along with PD had poorer quality of life outcomes than those with good

70 ce4less.com ce4less.com ce4less.com ce4less.com ce4less.com ce4less.com healthy nutrition. Nutritional status is fundamental to quality of life should be considered when planning total care of people with Parkinson’s disease. Another study focus on people with PD found direct correlations between nutritional status and disease duration, severity of motor and psychiatric symptoms and fatigue.

Physical And Exercise Therapy

Physical and exercise therapy can have a significant impact on frequency of falls, improve gait, posture and flexibility, improve movement initiation and improve the overall quality of life.131,136-139 A recent review provided a three- step clinical tool used to accurately predict the risk of falls. In the PD- affected population, falls are frequent and can result in significant and severe consequences including injuries, pain, loss of quality of life, loss of independence, limitation of activities, increased caregiver stress and death. The best single predictor of fall risk is the history of falls. The authors provided a three-step assessment in determining the risk of a fall. The test was developed by the MDS and is performed while the patient is “on” medication.

• Step 1: The patient is asked “Have you fallen in the last 12 months” If the answer is “yes” a score of 6 is given. (No= 0 points) • Step 2: The patient is asked “Have you experienced any freezing of gait in the past month?” If the answer is “yes” a score of 3 is given. (No= 0 points) • Step 3: Record that time it takes for the individual to walk past the 4 m mark of a 6 m long path. If the patient takes longer than 3.6 seconds to pass the 4 m mark, a score of 2 is given if the time is shorter than 3.6 seconds, a score of 0 is given. 71 ce4less.com ce4less.com ce4less.com ce4less.com ce4less.com ce4less.com

• A cumulative score of “0” indicates a low (17%) risk of a fall. If the cumulative score is between 2 and 6, a moderate (25%) risk of a fall is indicated. If the cumulative score is greater than 8, a high (85%) risk of a fall is indicated.

Risk factors for falls may be remedied or not (fixed). Fixed risk factors include a history of falls, higher doses of levodopa, severity of disease and duration of disease. Impulsivity may also contribute to a risk of falls. Age and gender are not fixed factors, but impaired balance, cognitive impairment and freezing of gait are. These last three are potentially remediated with physical intervention.

Recent studies have indicated that 2-year behavioral coaching programs designed to increase physical activity without increasing the rate of falls are successful. Programs that included challenges to balance, for example, supervised Tai chi classes, were more successful in reducing falls than those that did not include a balance challenge. External focus (i.e., visible target lines, paced auditory signals) appears to be an important in reducing postural instability, verbally directing the patient to be attentive to the effects of movement external to the patient has measurable benefits. A recent systematic review of the effects of external (visual, auditory or sensory) cues on gait parameters also concluded that external cues are effective for improving the gait parameters and psychomotor performance of PD patients. More studies are needed to verify how this type of treatment could improve the quality of life of patients with PD.

A recent systematic review indicated that progressive resistance exercises can also improve both strength and physical performance. There was however, little or no carryover for all measures of physical performance. Progressive resistance exercise was effective in improving walking. 72 ce4less.com ce4less.com ce4less.com ce4less.com ce4less.com ce4less.com

Exercise based computer games (exergaming) is an emerging rehabilitation tool. Exergaming can include the Nintendo Wii, Kinect and other systems and can impact gait, balance and strength. The games are driven by physical movements of the gamer and increase motivation to exercise and to get engaged. A recent systematic review of the relatively sparse literature concluded that exergaming was a feasible tool for rehabilitation, but there were significant safety and efficacy questions. Other therapies, such as dance therapy and aquatic physiotherapy have shown significant promise as well.

Novel Therapies: Agents and Targets

Novel agents and targets are currently being studied for safety and effectiveness for the treatment of PD. These are highlighted here.7,80

Adenosine Receptor Antagonists (A2A)

On binding to its receptor at GABAergic neurons, adenosine stimulates GABA release and is linked to D2 receptors. Adenosine receptor inhibitors include Istradefylline, a caffeine analog. Several clinical trials have indicated that istradefylline may be effective in decreasing “off” time, but the FDA found that the evidence was insufficient for approval. Other investigative drugs that can inhibit adenosine receptors are preladenant and tozedelant.

Glutamate Release Inhibitors

Safinamide is currently in Phase III clinical trials. Safinamide is a selective and reversible MAO-B inhibitor, blocks voltage-dependent Na+ and Ca2+ channels and inhibits the release of glutamate. Animal studies have indicated that safinamide can reverse the motor response after prolonged levodopa treatment in dopamine depleted mice and rats. Safinamide and

73 ce4less.com ce4less.com ce4less.com ce4less.com ce4less.com ce4less.com another glutamate release inhibitor, zonisamide, can enhance dopamine release in animal models. Neural Transplants

Neural transplants, to date, have shown no clear benefit. These include fetal dopaminergic cells, retinal pigment epithelial cells, and new cell sources. New cell sources involve human embryonic stem cells (hESC), which are pluripotent stem cells derived from blastocysts, induced pluripotent stem cells (iPSC), and somatic cells (i.e., fibroblasts), which can be reprogrammed to pluripotentiality.

Gene Therapy

To date, there have been nine gene therapy trials. None of these trials have shown significant benefit for PD. It should be mentioned, however, that these studies did demonstrate generation of biologically active proteins affecting structures deep in the human brain.

Future Directions In Parkinson’s Disease

Future directions in the treatment of PD include improvements and refinements in existing therapies as well as novel therapies such as medications against new targets, gene therapy, neural transplants, better defined DBS and others.140,145-151

There is also a continuing need to develop approaches for neuroprotection. Natural products such as CoQ10, Vitamin E, green tea and creatine or natural product analogs and minocycline have shown great promise in vitro and in animal studies, yet have failed to show significant effects in clinical trial. There are major limitations in developing and in studying neuroprotective agents, including an incomplete understanding of the neurophysiological processes underlying the development of PD. In addition, 74 ce4less.com ce4less.com ce4less.com ce4less.com ce4less.com ce4less.com there may be several different underlying processes occurring in PD. A further limitation is the lack of a reliable animal model in which to test either neuroprotective candidates or drug candidates.

Cannabinoids provide a set of potential candidates, though cannabinoid research remains limited. Δ9-tetrahydrocannabinol (THC) has been shown to be potentially neuroprotective in both animal and cell culture models via activation of the nuclear receptor peroxisomal proliferator-activated receptor γ (PPAR-γ). Also, IPX066 is an extended release levodopa-carbidopa, which has been shown to provide clinical benefits recently.

In one study, IPX066 reached therapeutic levels within 1 hour and maintained these levels for 4-5 hours. Patients converting to IPX066 had significantly improved UPDRS Part III scores, with over 65% of patients expressing preference over other levodopa-carbidopa preparations and over 68% of patients experiencing meaningful clinical benefit. Another treatment option is XP21279, which is a sustained-release prodrug (ester conjugate) of levodopa. XP21279-carbidopa has been found to decrease “off” time, though the response was not significant.

Glutamate antagonists, AFQ056 (Mavoglurant) combined with levodopa was evaluated in a recent study. The study was limited by low patient numbers and conflicting outcomes data, but the authors concluded that mavoglurant combined with higher doses of L-dopa may be effective treatment for L- dopa-related motor fluctuations and dyskinesias seen in PD patients. Phase II clinical trials are currently underway. There are many other areas of active research that are not included here. However, suffice to say that gene and neural transplant therapies have not provided clear evidence of benefit. These approaches have been shown to be safe and well-tolerated but this

75 ce4less.com ce4less.com ce4less.com ce4less.com ce4less.com ce4less.com does suggest that gene therapy and neural transplant approaches show promise for the treatment of PD. Summary

Parkinson’s disease is a progressive debilitating neurodegenerative disease that affects dopaminergic neurotransmission with primary symptoms of bradykinesia, rest tremor, and rigidity. Motor fluctuations are a common adverse effect to dopaminergic medications and may take months or years to develop. When assessing motor fluctuations, the clinician will record ‘on’ periods, which are those times when a patient is experiencing good control of symptoms with the medication, and ‘off’ periods, which are those times when the medication is wearing off or if symptoms are resurfacing.

Levodopa-induced dyskinesia is present when levodopa doses are at their peak. In the absence of peak-dose dyskinesias, the approaches are relatively straightforward. There are frequently unsatisfactory adjustments to pharmacological treatments, progressively compromising a patient’s quality of life. Other non-pharmacological treatments are available such as deep brain stimulation (DBS) that targets different brain structures to treat advanced PD as well as other movement, epilepsy or psychiatric disorders. Alternative and complimentary therapies have also been used to treat PD. Future directions in the treatment of PD include improvements and refinements in existing therapies as well as novel therapies such as medications against new targets, gene therapy, neural transplants, better- defined DBS and others.

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Reference Section

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