Medical treatment of the motor features of Parkinson disease

Pharmacologic agents

Disease-modification is a term used to indicate slowing of clinical worsening and is not equivalent to neuroprotection (slowing of disease pathologic progression). All clinical trials discussed later were designed to test disease modification. In this chapter, we will use the term “neuroprotection” instead of “disease modification” in an effort to use just one label. Neuroprotection can be divided into at least three different classes of action: slowing the pathogenetic cascade that leads to cell death so that the natural history of the disease is less progressive (neuroprotection), restoring injured dysfunctional neurons to good health (neurorescue, neurorestoration), and replacing dead neurons ( Fig. 6.2 ).

Currently, despite many clinical studies, no agent has demonstrated restorative properties or efficacy in slowing progression of PD ( Table 6.1 ). In most of the studies in Table 6.1 , worsening of severity of PD was measured quantitatively by the Unified Parkinson’s Disease Rating Scale (UPDRS) [ ]. Drugs that have been specifically evaluated in controlled clinical trials for slowing disease progression include selegiline and tocopherol ( ), selegiline alone ( ; ; , ); TCH346 (an antiapoptotic propargyline that inhibits glyceraldehyde 3-phosphate dehydrogenase) ( ; ; ), riluzole ( ), neuroimmunophilin ( ), coenzyme Q ₁₀ ( ; ), glial cell line–derived neurotrophic factor (GDNF) ( ; ), rasagiline ( ; ), minocycline and the energy enhancer creatine ( ; ; ), CEP-1347 (an inhibitor of the mixed lineage kinase-3 family) ( ), neurturin ( ; ), GM1 ganglioside ( ), pramipexole ( ), coenzyme Q10 ( ), intranasal reduced glutathione ( ), pioglitazone ( ), exenatide ( , ; ), isradipine ( , ; ), inosine ( ; Press Release, 2019A), isradipine ( ), and levodopa ( ; ; and most recently nilotinib ( (see Table 6.1 ).

Some controlled studies of disease-modifying treatments have demonstrated success in achieving the primary outcome, but each of these was confounded by the symptomatic effect of the agent being tested, and none are approved for neuroprotection ( Table 6.2 ).

Despite the fact that many of the drugs listed previously showed promise in animal models and in small early studies, each failed in larger controlled trials or were confounded by the effect of the drug in improving motor symptoms. In part, some of the reasons for these failures may be the lack of appropriate animal models for progressive PD, the heterogeneity of PD that suggests there may be different mechanisms of disease, and lack of a biomarker for progression of disease.

Several studies are currently in progress looking at newer agents to determine whether they have such a disease-modifying effect. Alpha-synuclein antibodies and other antisynuclein strategies are currently being investigated in clinical trials ( ; ).

Exercise

Although exercise is important to everyone to maintain health, it may be particularly helpful in PD. However, despite the increasing literature citing the benefits of exercise, many do not participate in a regular exercise regimen. A cross-sectional study noted that the obstacles to exercise in PD include lack of certainty of the benefit, lack of time, and fear of falling during exercise ( ). Many types of exercise have been reported to improve the symptoms of PD and reduce falls ( , , ; ; ; ; ; ; ; ; ). In fact, tai chi, progressive resistance, treadmill, forced bicycle riding, tango, and many other forms of exercise have improved symptoms. However, most of these require regular exercise of approximately 3 to 4 times per week for at least 30 minutes. The benefits from exercise tend to wane if the patient fails to adhere to the program. Freezing of gait, which is a difficult parkinsonian motor feature to treat, was found to be reduced in a controlled clinical trial evaluating exercises with motor complexity – so-called adapted resistance training with instability ( ).

Physical therapy is one technique that can motivate patients to exercise. However, many become noncompliant after completion of the therapy. Physical therapy strategies can lead to improved activities of daily living (ADLs), improved gait, and treatment of musculoskeletal issues that are secondary to PD, including frozen shoulder and back pain.

PD leads to decreased motivation and increased passivity. An active exercise program, even early in the disease, can help overcome this. Furthermore, such a program involves patients in their own care, allows muscle stretching and full range of joint mobility, and enhances a better mental attitude toward fighting the disease. By being encouraged to take responsibility in fighting the devastations of the disease, the patient becomes an active participant. Physical therapy, which can be implemented in the form of a well-constructed exercise program, is useful in all stages of disease. In early stages, a physical therapy program can instruct the patient in the proper exercises and the regimen forces the patient to exercise if he or she lacks the motivation to exercise on his or her own. In advanced stages of PD, physical therapy may be even more valuable by keeping joints from becoming frozen and providing guidance how best to remain independent in mobility. Therefore, exercise is beneficial in both the early and later stages. It has been shown that PD patients who exercise intensively and regularly have better motor performance [ ; ; ; ; ] and quality of life [ ; ].

Three relatively new exercise programs have become popular with patients: Lee Silverman Voice Treatment (LSVT) BIG ( ), Rock Steady Boxing, and dancing. When patients are in an exercise community, it appears that they are more likely to continue to exercise and view it as beneficial. The motivation provided by a group session that is ongoing is likely one of the reasons that these are successful. At this time, there are few studies of these interventions

A number of reports suggest that exercise may be more than a symptomatic treatment. Investigators have determined that exercise may have positive effects on the underlying pathophysiologic processes of PD. In animal models, there is an increase in neurotrophic factors, reduced neuroinflammation, and a reversal of dendritic spine loss in the striatum ( ; ; ; ; ). Basic scientific studies have discovered that exercise, particularly enriched exercise, can reduce the loss of dopaminergic neurons after 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) exposure. When such exercise is initiated shortly after rodents were given experimental lesions of the nigrostriatal dopamine pathway, the result was a significantly lesser amount of damage to the dopamine pathway ( , , ; ; ; ; ). The mechanism appears to be to the induction of increased trophic factors, such as GDNF ( ; ) and brain-derived neurotrophic factor (BDNF) ( ). Exercise also appears to reverse dendritic spine loss in direct and indirect striatal medium spiny neurons ( ) and to enhance neuroplasticity in motor and cognitive pathways ( ). An imaging study found that habitual exercisers had greater dopamine release in the caudate nuclei than do sedentary subjects when measured before and after stationary cycling ( ).

Individualize therapy

The treatment of PD needs to be individualized; that is, each patient presents with a unique set of symptoms, signs, response to medications, and a host of social, occupational, and emotional problems that need to be addressed. Although early in the disease the treatment may be straightforward, with progression of PD the occurrence of motor complications, drug side effects, and nonmotor issues such as dementia, depression, and apathy, increases the complexity of decision making when selecting pharmacologic interventions. The major goal is to keep the patient functioning independently as long as possible. Determine what the issues are for the individual patient by asking the patient to list the specific symptoms that trouble him or her the most ( ). Attempt to treat the most troublesome symptoms; this is the way to maximize quality of life.

Dopaminergic Agents ( Table 6.4 )

Enzyme inhibitors

Besides being metabolized by aromatic amino acid decarboxylase (often called dopa decarboxylase), levodopa is also metabolized by catechol-O-methyltransferase (COMT) to form 3-O-methyldopa. Three COMT inhibitors are currently available: tolcapone, entacapone, and opicapone. These agents extend the plasma half-life of levodopa with only a small increase in its peak plasma concentration, and can thereby prolong the duration of action of each dose of levodopa. These drugs are used in conjunction with levodopa to reduce the wearing-off effect ( ), a common motor fluctuation adverse effect of levodopa therapy. The net effect with multiple dosings per day, though, is to elevate the average plasma concentration while smoothing out the variations in the concentration. Tolcapone has two potential adverse effects that need to be explained to the patient. The most serious is that a small percentage of patients will develop elevated liver transaminases, and patients need to have baseline and follow-up liver function tests. Death from hepatic necrosis has occurred in three patients who had no liver function surveillance ( ). Entacapone has not been shown to induce these hepatic changes. In addition with tolcapone, a small percentage of patients will develop diarrhea that does not appear for about 6 weeks after starting the drug. The diarrhea can be explosive, so the patient might not have any warning. Entacapone appears not to have these adverse effects. Many clinicians think that tolcapone is more effective than entacapone in reducing motor fluctuations, but one should not prescribe the former unless the latter has not been effective in relieving wearing off. Patients on entacapone can be easily switched to tolcapone if the former had less than the desired effect, and a double-blind comparison showed tolcapone to be slightly more effective in reducing the amount of “off” time ( ). If tolcapone is to be used, we advise starting at a low dose of 100 mg/day and increase gradually to 100 mg three times daily. Entacapone has a short half-life, so a dose of 200 mg is taken with each dose of levodopa ( ). One formulation (Stalevo) combines carbidopa, levodopa, and 200 mg entacapone into a single tablet; the dose of a tablet of Stalevo represents the amount of levodopa in the tablet.

Adding entacapone to patients on levodopa who are not experiencing motor fluctuations did not add any improvement to motor performance in one study ( ) but improved the ADLs score in another ( ). In the FIRST-STEP study, levodopa/carbidopa/entacapone (LCE) 100/25/200 mg 3 times daily, was compared with levodopa/carbidopa (LC) 100/25 mg 3 times daily in patients with early PD for 39 weeks ( ). LCE treatment resulted in slightly better Unified Parkinson’s Disease Rating Scale (UPDRS) Part II ADLs scores ( P = 0.025) but not Part III motor scores.

The concept that intermittent brain levels of levodopa and dopamine contribute to the development of motor complications (see later in discussion of advanced PD) has led to the concept that continuous dopaminergic stimulation may avoid these complications from levodopa. So far, one study (STRIDE-PD) testing this hypothesis has yielded the opposite effect, that is, an earlier onset of dyskinesias ( ). A total of 747 patients with early PD were randomized to LCE 100/25/200 mg or LC 100/25 mg with flexible dosing to reach 400 mg/day, with a dose 3.5 hours apart. The results showed that time to dyskinesia was statistically significantly shorter in LCE-treated patients compared with LC-treated patients. The incidence of dyskinesia during the study period was higher in LCE-treated patients in comparison to the LC group.

Nondopaminergic Agents for Motor Symptoms

Some nondopaminergic agents (see Table 6.8 ) are also useful to treat motoric PD symptoms, particularly antimuscarinic drugs (commonly referred to as anticholinergics), which have been widely used since the 1950s, but these are much less effective than the dopaminergic agents, including amantadine. The original use of antimuscarinic alkaloids date back to the time of Charcot, and synthetic agents became available and popular in the 1950s (see review by ). Antimuscarinic drugs are somewhat helpful in reducing all symptoms of PD, but they have found special favor in reducing the severity of tremor. However, because of sensitivity to memory impairment in all groups and hallucinations in the elderly population, antimuscarinic drugs usually should be avoided in patients over the age of 70 years. The antihistaminics (diphenhydramine, orphenadrine, and others), tricyclics (amitriptyline and others), and cyclobenzaprine (Flexeril) have milder anticholinergic properties that can make them useful in PD, particularly in older patients who should not take the stronger anticholinergics because of their propensity to impair short-term memory at that age level.

Amantadine, listed in Table 6.4 as a dopaminergic agent, is listed also in Table 6.8 because it has antiglutamatergic effects; this property appears to account for its usefulness in reducing choreic dyskinesias induced by levodopa ( ; ; ; ). An extended-release form of amantadine was found to be effective to reduce levodopa-induced dyskinesias in a controlled clinical trial ( , ) and has been approved by the FDA for this indication. Dextromethorphan is another antiglutamatergic agent, and it has been found effective in reducing the severity of dyskinesias by 50% ( ).

Another useful class of drugs is the benzodiazepines to decrease parkinsonian tremor that is exacerbated by stress. These drugs reduce anxiety and by calming a patient provide a lessening of tremor. Diazepam is usually well tolerated and does not exacerbate parkinsonian symptoms, whereas chlordiazepoxide can ( ). Lorazepam and alprazolam are other useful benzodiazepine agents; the latter has the added benefit of being short-acting, so it can be used when needed. It also has some antidepressant effects. The benzodiazepines can cause drowsiness, so it is best to start with a small dose and increase it if tolerated. The muscle relaxants listed in Table 6.8 might help in treating “off” and peak-dose dystonias. Because oxidative stress appears to play a role in the pathogenesis of PD, high dosages of antioxidant vitamins, tocopherol, and coenzyme Q10 have been tried for patients with PD and failed in clinical trials ( ; ).

Stress, excitement, and anxiety make parkinsonian symptoms worse, especially tremor. In fact, tremor that is otherwise well controlled with medication can reemerge under stress, excitement, and anxiety. The benzodiazepines, by reducing anxiety, can partially offset this worsening of tremor. Apathy and fatigue are common in PD, and no medication as yet has been found satisfactory.

Adenosine A _2A receptors are located on gamma-aminobutyric acid (GABA) neurons in the striatum and antagonize the effect of dopamine on these neurons ( ). Antagonizing adenosine A2A receptors has a behavioral effect similar to enhancing dopaminergic transmission. Several of these receptor antagonists ( Table 6.8 ) have undergone clinical trials for patients with motor fluctuations ( ; ; ; ; ), but the results were mixed, with insufficient relief of fluctuations and enhanced dyskinesias ( ). However, after further clinical trials, istradefylline was found effective in reducing clinical fluctuations ( ) and was approved for this indication by the FDA in 2019 under the label of Nourianz. Because of its favorable side effect profile, istradefylline may be particularly useful in elderly patients with troublesome motor fluctuations who may have comorbid depression or cognitive impairment ( ).

Various sleep problems are encountered in PD. Excessive drowsiness can occur after a dose of levodopa or dopamine agonist. Modafinil and methylphenidate can sometimes help overcome this problem. Insomnia needs to be treated, otherwise quality of life suffers and daytime sleepiness is enhanced. For insomnia, mild hypnotic drugs such as melatonin, antihistamines, trazodone, and mirtazapine can be used with satisfying results. Stronger hypnotics, such as zolpidem and benzodiazepines, can be safely used if the milder drugs are not effective.

MAO-B inhibitors: selegiline and rasagiline

As can be seen from Table 6.2 , the MAO-B inhibitors that have been tested in neuroprotection trials were all able to slow the rate of worsening of the motor features of PD. The irreversible inhibitors, selegiline and rasagiline are available commercially, but even lazabemide, a reversible MAO-B inhibitor, never marketed, also was effective. Not a single study with an MAO-B inhibitor failed a clinical trial in being superior to a placebo. The major question is whether this effect is all from its symptomatic effect or some of its benefit is from a neuroprotection (disease-modification) effect.

The first controlled clinical trial for the purpose of evaluating medications as neuroprotective agents for PD was the test for selegiline in the Deprenyl and Tocopherol Antioxidative Therapy of Parkinsonism (DATATOP) study ( , , ). Selegiline was called deprenyl at the time the trial was begun. Selegiline is a propargyline drug and has a long duration of action (MAO-B inhibition half-life of 40 days) ( ). The DATATOP study evaluated the antioxidant, alpha-tocopherol (vitamin E), along with selegiline in a 2 × 2 design. Patients were enrolled in the study early in the course of their illness and did not require symptomatic therapy. They were placed on selegiline (5 mg twice daily), alpha-tocopherol (1000 IU twice daily), the combination, or double placebo, with approximately 200 subjects in each of the four treatment arms. The primary endpoint was the need for dopaminergic therapy, that is, levodopa. The study showed that tocopherol had no effect in delaying parkinsonian disability, but selegiline delayed symptomatic treatment by 9 months ( Fig. 6.4 ) ( ). It also reduced the rate of worsening of the UPDRS by half ( Table 6.9 ). Other investigators subsequently conducted other studies testing selegiline, showing similar beneficial results ( ; ; , ).

Because selegiline has a mild symptomatic effect that is long lasting ( ), one might explain its ability to delay progression of disability entirely on this symptomatic effect. In favor of some neuroprotective effect is that after 2 months of washout of the drug, patients had slightly milder PD than did those on placebo ( ). But because of selegiline’s very long duration of action as an inhibitor of MAO-B ( ), this observation could represent an insufficient washout period. Furthermore, selegiline’s benefit in delaying the introduction of levodopa gradually diminishes over time ( ), with the best results occurring in the first year of treatment. The odds ratio increased from 0.35 for the first 6 months, to 0.38 in the second 6 months, to 0.77 in the third 6 months, and to 0.86 after 18 months. Follow-up of DATATOP subjects showed that placebo-treated subjects fared better than selegiline-treated subjects when the drug was reintroduced after a 2-month washout period and that the two groups were identical in developing levodopa complications ( ). The net understanding by the year 2000 was that there is no convincing evidence that selegiline delayed the need for levodopa because of any protective effect; all results could be those of a drug with a continuing mild symptomatic benefit.

On the other hand, basic scientific research was finding that in animal models tiny doses of selegiline have a neuronal rescue effect ( ). This effect is separate from its MAO inhibitor mechanism of action. Ultimately this finding led to investigations of other agents for their rescue effect, resulting in the discovery of a propargyline drug without MAO inhibition (TCH346) that was tested in a clinical trial ( , ). This drug failed to be better than placebo ( ).

When the results of the DATATOP study were analyzed to better understand the development of freezing of gait, it was discovered that the group who were treated with selegiline had a statistically significantly decreased risk for developing freezing of gait ( Fig. 6.5 ) ( ). It could not be discerned whether this benefit was because of selegiline’s mild symptomatic benefit or of some unknown neuroprotection effect. Whichever it was, the authors concluded that one should consider using selegiline in patients who are likely to develop freezing of gait those with (absence of tremor, gait involvement as the initial symptom).

Subsequently, based on the BLIND-DATE study, there is evidence that the decreased risk for freezing of gait with selegiline is not simply from its symptomatic effect as an enhancer of dopamine. The investigators of the DATATOP study, while continuing to follow their subjects, carried out a rerandomization of the subjects into a new controlled trial (called the BLIND-DATE study). A total of 368 subjects who were now taking both selegiline and levodopa therapy agreed to be randomized to either selegiline or placebo while remaining on open-label levodopa. The results were dramatic. Over an almost 2-year period, the subjects on selegiline required a lower dosage of levodopa, had a slower rate of worsening of symptoms and signs of PD ( Table 6.10 ), and had less freezing of gait ( Fig. 6.6 ) ( ). These results support the view that selegiline does provide some neuroprotective effect or else it has a symptomatic effect separate from a dopaminergic effect. The possibility that this benefit is derived from an antiapoptotic effect rather than its antioxidative effect is discussed later.

A similar study was carried out in Sweden by Palhagen and colleagues (2006), who followed patients for at least 7 years after they entered a controlled clinical trial evaluating selegiline versus placebo in those with early, untreated PD. Then, when any subject required symptomatic therapy, open-label levodopa was added while the blind was maintained on selegiline versus placebo. During the 7 years of follow-up from the start of the study, the selegiline-treated group had a statistically significantly slower rate of worsening of clinical signs and symptoms as measured by UPDRS scores. Like the study by Shoulson and colleagues (2002) mentioned earlier, this also shows the added benefit that selegiline provides in slowing clinical symptoms. Whether this can be attributed to a neuroprotective effect or to a symptomatic effect that does not appear to be through dopamine is undetermined by the two studies.

The safety of selegiline was raised, though, in an open-label clinical trial in the United Kingdom ( ). The use of selegiline when combined with levodopa was reported to be associated with a higher mortality rate than was seen in the patients assigned to levodopa treatment alone. Analysis of this result by others found a number of flaws in the study to refute this conclusion ( ). The U.K. investigators followed up their report with a more detailed analysis of the cause of death (Ben- ). The excess mortality in the selegiline plus levodopa group was greatest in the third and fourth years of treatment. The cause of the increase in deaths showed the excess to be from PD only and to occur particularly in patients with dementia and a history of falls. No significant differences in mortality were found for revised diagnosis, disability rating scores, autonomic or cardiovascular events, other clinical features, or drug interactions. Other studies with selegiline have failed to find any excess mortality from the combination treatment with levodopa ( ; ; ). After being followed by the Parkinson Study Group an average of 8.2 years, the subjects in the DATATOP study showed no difference in mortality between the groups assigned to treatment with selegiline, tocopherol, or placebo; the death rate averaged 2.1% per year ( ), much lower than in the U.K. study.

A meta-analysis of 17 controlled clinical trials involving MAO-B inhibitors found that no significant difference in mortality existed between patients on the inhibitors compared with control subjects ( ). The analysis also found that subjects randomized to MAO-B inhibitors had significantly better total scores, motor scores, and ADL scores on the UPDRS at 3 months compared with patients taking placebo; they were also less likely to need additional levodopa or to develop motor fluctuations. No difference existed between the two groups in the incidence of side effects or withdrawal of patients.

High-dosage tocopherol also has been suggested to increase mortality, but analysis of the DATATOP cohort followed for up to 13 years failed to find any difference in mortality between the groups on vitamin E and the group on placebo ( ).

In an analysis of retrospective observational data from Scotland ( ) comparing PD patients with a comparable control population, the patients with PD had a higher rate of mortality than those without PD (rate ratio [RR], 1.76; 95% confidence interval [CI], 1.11–2.81). There was significantly greater mortality in monotherapy (RR, 2.45, 95% CI, 1.42–4.23) relative to the comparators, adjusting for previous cardiovascular drug use and diabetes. However, there was no significant difference in mortality in patients with PD who received combination therapy of selegiline with levodopa and other drugs in relation to the comparators (RR, 0.92, 95% CI, 0.37–2.31). Thus, from this study, selegiline did not increase the mortality rate, whether used as monotherapy or in combination with levodopa. In fact, levodopa monotherapy had the highest mortality rate.

Rasagiline, based on the delayed-start studies, TEMPO ( ) and ADAGIO ( ), also can reduce the rate of clinical worsening in patients with early PD. But there were inconsistent outcomes between these two studies. In TEMPO, the 2-mg dose of rasagiline had a superior result compared with the 1-mg dose. In ADAGIO, only the 1-mg dose was superior to placebo; the 2-mg dose was no better than placebo ( Fig. 6.7 ). Starting a symptomatically effective drug early does not automatically lead to a reduced rate of clinical worsening as tested by the delayed-start design. For example, pramipexole, an effective dopaminergic agent, does not give a superior clinical result if started early compared with starting it later ( ). Thus, there would appear to be a special property of the MAOIs to be able to delay clinical worsening in a delayed-start study.

As mentioned earlier, the dose of selegiline and rasagiline should not exceed their specificity as selective type B inhibitors of MAO. Selegiline greater than 10 mg/day and rasagiline greater than 2 mg/day will also inhibit MAO-A. In one example, a woman given rasagiline at 4 mg/day in the presence of levodopa therapy developed the serotonin syndrome of hyperpyrexia, confusion, agitation, and episodic periods of unconsciousness ( ). Because selegiline is metabolized to L-amphetamine and L-methamphetamine, insomnia could develop and one should avoid taking it late in the day. It may be necessary to limit selegiline to 5 or 10 mg in the morning only if insomnia is a problem. Male impotence is not common with MAO inhibitors. In the presence of levodopa, MAOIs potentiate levodopa’s effect, and lower doses of levodopa can usually be achieved ( ; ). Selegiline does not prevent the development of levodopa-induced complications of fluctuations and dyskinesias ( ). Selegiline decreases the risk for patients developing freezing of gait ( ; ). It is not clear if rasagiline has this ability. Interestingly, MAO-A inhibitors, but not MAO-B inhibitors, have been shown to reduce stress-induced freezing behavior in rats ( ).

The DATATOP study showed that selegiline inhibits MAO activity by about 20% in the CNS ( ). Because the original premise for the DATATOP study was that selegiline might be neuroprotective by inhibiting MAO (reducing formation of hydrogen peroxide and thereby decreasing oxidant stress), the CSF analysis of homovanillic acid indicates that selegiline is a poor inhibitor of CNS MAO. This finding could explain the lack of success of selegiline as a powerful neuroprotective agent. Whether a more potent MAOI could be more successful remains to be determined. In the meantime, it is reasonable for patients to consider an inhibitor of both types A and B, as possibly augmenting inhibition of MAO in brain. However, such MAOIs can induce the cheese effect, so a low-tyramine diet needs to be followed. Such MAOIs can be used only in the absence of levodopa because the presence of levodopa will create marked blood pressure fluctuations.

Another MAO-B inhibitor, safinamide, offers modest symptomatic benefit of PD ( ; ; ), but it has not been tested for a potential neuroprotective effect. Safinamide is a reversible MAO-B inhibitor, in contrast to selegiline and rasagiline, which are irreversible inhibitors. Safinamide also blocks sodium voltage-sensitive channels and modulates stimulated release of glutamate ( ). Thus, there may other clinical benefits or adverse effects from this drug. It was approved by the FDA in 2017 as an add-on drug for treating the wearing-off effect.

Dopamine agonists

Dopamine agonists are the next most powerful drugs after levodopa in reducing the motor symptoms of PD. Controlled clinical trials compared four different dopamine agonists against levodopa in patients with PD who were in need of symptomatic therapy: cabergoline and levodopa ( ), ropinirole and levodopa ( ), pramipexole and levodopa (the CALM-PD trial) ( ), and pergolide and levodopa ( ). The clinical outcomes of these studies are discussed later.

In this section, the results of the neuroimaging component of these trials are discussed. In the CALM-PD (pramipexole versus levodopa) trial, the 4-year imaging results show a statistically significant lesser rate of decay of dopamine transporter (DAT) binding (β-CIT SPECT) (a marker of integrity of nerve terminals of the dopaminergic nigrostriatal fibers) in the striatum in the group originally assigned to pramipexole treatment ( Fig. 6.8 ) ( ). A separate study evaluating FDOPA positron emission tomography (PET) scans, a marker of dopa uptake and dopa decarboxylase activity, showed a similar statistically significant lesser rate of decay of labeling in the striatum in a controlled trial in the group assigned to ropinirole compared with the group assigned to levodopa therapy ( ).

Because there was no placebo comparator in either study, interpretation is difficult. Whether dopamine agonists slow the rate of progression of PD, whether levodopa hastens it, and whether both explanations are playing a role are possibilities. Another possibility would be a pharmacodynamic effect on the DAT and dopa decarboxylase by either the agonists or levodopa. For example, if levodopa downregulated the DAT, β-CIT SPECT binding would be reduced. If levodopa downregulated dopa decarboxylase, FDOPA PET binding would be reduced. Short trials of levodopa showed no change in these imaging markers, so there is no evidence that levodopa affects either type of imaging study in such a pharmacologic manner. But a consensus conference concluded that there is insufficient information about the effect of medications on dopaminergic imaging to recommend neuroimaging as a biomarker for disease progression in the presence of medication ( ). Without knowing whether the agonists actually slow the rate of progression, it is not possible to recommend the starting treatment on the basis of these results alone. Pramipexole was later tested in a delayed-start clinical trial and failed to show any slowing of PD ( ).

Inhibiting calcium entry

Substantia nigra pars compacta (SNc) dopamine neurons are autonomously active; that is, they generate action potentials at a clock-like 2 to 4 Hz in the absence of synaptic input ( )]. In this respect, they are much like cardiac pacemakers. Juvenile dopamine-containing neurons in the SNc use sodium influx as the pacemaking mechanisms common to neurons not affected in PD, but the sodium mechanism remains latent in adulthood ( ). Instead, the autonomous activity is generated by Ca ⁺⁺ influx ( ; ; ). The SNc dopamine neurons rely on L-type Ca(v)1.3 Ca ⁺⁺ channels. With increased intracellular calcium, mitochondria function can be affected with increased demand on oxidative phosphorylation, leading to increased production of reactive oxygen species and eventually cellular damage. As the cells undergo more stress over time, they thus “age faster.” This would be a link with the risk factor of age ( ). Blocking Ca(v)1.3 Ca ⁺⁺ channels in adult neurons induces a reversion to the juvenile form of pacemaking. Such blocking (“rejuvenation”) protects these neurons in both in vitro and in vivo models of PD, pointing to a new strategy that could slow or stop the progression of the disease ( ; ).

As it turns out, use of calcium channel blockers for treating hypertension has been shown to be associated with less risk for developing PD in two database-mining studies ( ; ), but not in a third ( ). A clinical trial to evaluate the dihydropyridine isradipine, a calcium channel blocker, was shown to be well tolerated ( ; ), but the results of a phase III clinical trial failed to show any difference between isradipine and placebo in the progressive worsening of PD ( ; Parkinson Study Group STEADY-PD III Investigators, 2020) (see Table 6.1 ).

Uric acid

Because elevation in blood uric acid has been thought to be potentially neuroprotective, the prourate drug inosine has been tested in patients with early-stage PD, but the phase III trial (SURE-PD) ended early because the investigators thought they would not be able to show that inosine slows Parkinson’s progression ( https://www.michaeljfox.org/news/parkinsons-inosine-trial-ending-early ) (see Table 6.1 ).

Conclusions on treating Early-Stage PD

In this earliest stage of PD, we follow a recommendation that Fahn has advised, namely patients need to be informed about the disease and the advantages of a daily exercise program. Furthermore, although there is no medication proven to slow the worsening of the disease, it is reasonable to initiate therapy with a MAO-B inhibitor listed in Table 6.1 (selegiline or rasagiline) that has consistently been shown to reduce motor severity compared to a placebo, and may have some disease-modifying effect. Because selegiline has been the only drug shown in controlled clinical trials (even in the presence of levodopa therapy) to delay development of freezing of gait ( ; Fig. 6.6 ), Fahn prefers this medication.

Strategy

The mild stage of PD occurs when the signs and symptoms of the illness are beginning to interfere with daily activities or with quality of life. The judgment to initiate symptomatic drug therapy is made in discussions between the patient and the treating physician. According to a survey ( ) the most common problems that clinicians consider important for the decision to initiate symptomatic agents are (1) threat to employability; (2) threat to ability to handle domestic, financial, or social affairs; (3) threat to ability to handle ADLs; and (4) appreciable worsening of gait or balance. According to a Norwegian quality of life study ( ), the factors that produce the highest distress for PD patients compared with healthy elderly people are depressive symptoms, self-reported insomnia, and a low degree of independence, as measured by the Schwab and England scale. Severity of parkinsonian motor symptoms contributed, but to a lesser extent. A sense of lack of energy was seen in half of the PD patients compared with a fifth of controls, and this could be only partially accounted for by depressive symptoms and the UPDRS motor scores.

The choice of drugs to improve motor symptoms is wide (see Tables 6.4 and 6.8 ), but the degree of disability and the age (or mental acuity) of the patient are two critical factors in making the selection. If the delay in initiating symptomatic treatment was so prolonged that the symptoms threaten employment or endanger falling, one needs to begin levodopa to get a quick, effective response. The advantages of using levodopa when the symptoms are this pronounced, in preference to a dopamine agonist or other medications, are that a therapeutic response is both rapid and virtually guaranteed, because nearly all patients with PD will respond to levodopa and relatively quickly. In contrast, only a minority of patients with severe symptoms will benefit sufficiently from a dopamine agonist given alone, and it takes more time (often months) to build up the dose to adequate levels to discover this. If levodopa is to be used, inhibitors of type A MAO must be discontinued. If selegiline (or another selective type B MAOI) was the MAOI that was used, this drug can be continued.

If the symptoms are not severe enough to require levodopa and the patient is younger than 60 (younger than 70 if the patient is mentally young), we prefer to employ a dopa-sparing strategy to avoid, as long as possible, the development of levodopa-induced dyskinesias and motor fluctuations (mainly the wearing-off effect). These motor complications are more likely to occur in younger patients ( ; ; ; ). Besides MAO-B inhibitors, which the patient may already be taking, the choices are dopamine agonists, amantadine, and anticholinergics. Dopamine agonists are the most potent antiparkinsonian agents among this group of drugs. Four-year results of the pramipexole versus levodopa trial reveal that levodopa is clinically more potent but is also much more likely to induce dyskinesias and clinical fluctuations ( ). In general, for patients older than 70 years or those with any cognitive impairment, employ levodopa as the initial therapy. Not only is there less need for a dopa-sparing strategy in these elderly patients but they are also more susceptible to confusion, psychosis, or drowsiness from other antiparkinson drugs, including dopamine agonists. Levodopa provides the greatest benefit for the lowest risk of these adverse effects compared with the other drugs. Another consideration is for those patients who need to drive an automobile extensively for their work. The risk for falling asleep at the wheel is greatest for those taking dopamine agonists ( ; ).

Rationale for using a dopa-sparing strategy in young patients

As was mentioned earlier, patients younger than 60 years of age are particularly prone to develop the motor complications of fluctuations and dyskinesias ( ; ; ; ). Some physicians therefore recommend using a dopa-sparing strategy, rather than levodopa, in younger patients when beginning therapy, in an attempt to delay the onset of these problems ( ; ; ). But others prefer starting with levodopa ( ). A conference on this topic failed to produce a consensus ( ). There is evidence that duration and severity of disease is a more critical risk factor than duration of levodopa therapy in causing dyskinesias ( ).

Choice of drug when employing a dopa-sparing strategy