Faculty Bibliography

OBJECTIVE: To test the hypothesis that there are sex differences in cerebral energy metabolism in Parkinson's disease (PD). METHODS: Phosphorus magnetic resonance spectroscopy ((31)P MRS) was used to determine high-energy phosphate (phosphocreatine and ATP) and low-energy phosphate (free phosphate) levels in the striatum and temporoparietal cortical gray matter (GM) in 10 men and 10 women with PD, matched for age at onset, disease duration, and UPDRS scores. RESULTS: In the hemisphere more affected by PD, both ATP and high energy phosphate (HEP: phosphocreatine + ATP) content in striatum was 15% lower in men versus women with PD (p = .050 and p = .048, respectively). Similar decreases by 16% in ATP (p = .023) and 12% in HEP (p = .046) were observed in GM in men versus women with PD. In contrast, there were no detectable sex differences in ATP or HEP in healthy age-matched controls. CONCLUSIONS: Men with PD have lower levels of ATP and high energy phosphate than women in brain regions affected by PD. These findings suggest that there may be a greater burden of mitochondrial dysfunction in PD in men versus women with PD.

Dopamine agonists are effective treatments for a variety of indications, including Parkinson's disease and restless legs syndrome, but may have serious side effects, such as orthostatic hypotension, hallucinations, and impulse control disorders (including pathological gambling, compulsive eating, compulsive shopping/buying, and hypersexuality). The most effective way to alleviate these side effects is to taper or discontinue dopamine agonist therapy. A subset of patients who taper a dopamine agonist, however, develop dopamine agonist withdrawal syndrome (DAWS), which has been defined as a severe, stereotyped cluster of physical and psychological symptoms that correlate with dopamine agonist withdrawal in a dose-dependent manner, cause clinically significant distress or social/occupational dysfunction, are refractory to levodopa and other dopaminergic medications, and cannot be accounted for by other clinical factors. The symptoms of DAWS include anxiety, panic attacks, dysphoria, depression, agitation, irritability, suicidal ideation, fatigue, orthostatic hypotension, nausea, vomiting, diaphoresis, generalized pain, and drug cravings. The severity and prognosis of DAWS is highly variable. While some patients have transient symptoms and make a full recovery, others have a protracted withdrawal syndrome lasting for months to years, and therefore may be unwilling or unable to discontinue DA therapy. Impulse control disorders appear to be a major risk factor for DAWS, and are present in virtually all affected patients. Thus, patients who are unable to discontinue dopamine agonist therapy may experience chronic impulse control disorders. At the current time, there are no known effective treatments for DAWS. For this reason, providers are urged to use dopamine agonists judiciously, warn patients about the risks of DAWS prior to the initiation of dopamine agonist therapy, and follow patients closely for withdrawal symptoms during dopamine agonist taper.

Impulse control disorders (ICDs) are potentially serious side effects of dopamine agonist therapy in Parkinson's disease (PD), but prospective data are lacking about their incidence, time course, and risk factors. This work was a 4-year, prospective cohort study of outpatients with PD and no previous ICDs (N = 164). All subjects treated with a dopamine agonist during the study were followed longitudinally for new-onset ICDs. Baseline characteristics were compared in groups with (ICD+) and without (ICD-) subsequent ICDs. Forty-six subjects were treated with a dopamine agonist, including 25 who were newly treated and 21 who received ongoing dopamine agonist therapy. Of these 46 subjects, 18 (39.1%) developed new-onset ICDs. The timing of ICD onset varied from 3.0 to 114.0 months (median, 23.0) after initiation of dopamine agonist therapy. Baseline demographic characteristics were similar in ICD+ and ICD- groups. At baseline, ICD+ subjects had a greater prevalence of motor complications (61.1% versus 25.0%; P = 0.01) than ICD- subjects, despite comparable total dopaminergic medication usage in both groups (median, 150.0 versus 150.0 levodopa equivalents; P = 0.61). Compared with ICD- subjects, ICD+ subjects had a greater baseline prevalence of caffeine use (100% versus 66.7%; P = 0.007) and higher lifetime prevalence of cigarette smoking (44.4% versus 14.3%; P = 0.04). Peak dopamine agonist doses were higher in ICD+ than ICD- subjects (median 300.0 versus 165.0 L-dopa equivalents; P = 0.03), but cumulative dopamine agonist exposure was similar in both groups. In summary, the timing of new-onset ICDs in PD is highly variable. Risk factors include cigarette smoking, caffeine use, motor complications, and higher peak dopamine agonist dosage. (c) 2013 Movement Disorder Society.

Impulse control disorders (ICDs), such as compulsive gambling, buying, sexual behavior, and eating, are a serious and increasingly recognized complication of dopamine replacement therapy in Parkinson's disease (PD). Other impulsive-compulsive behaviors have been linked to dopaminergic medications; these include punding (stereotyped, repetitive, purposeless behaviors) and dopamine dysregulation syndrome (DDS; compulsive medication overuse). ICDs have been most closely related to the use of dopamine agonists (DAs), particularly at higher dosages; in contrast, DDS is primarily associated with shorter-acting, higher-potency dopaminergic medications, such as apomorphine and levodopa. Risk factors for ICDs may include male sex; younger age; younger age at PD onset; a pre-PD history of ICD(s); personal or family history of substance abuse; bipolar disorder; gambling problems; and impulsive personality traits. The primary treatment of ICDs in PD is discontinuation of DA therapy. Not all patients can tolerate this, however, due to worsening motor symptoms and/or DA withdrawal syndrome (a severe, stereotyped drug withdrawal syndrome similar to that of other psychostimulants). While psychiatric medications are frequently used to treat ICDs in the general population, there is no empirical evidence to suggest that they are effective in PD. Given the paucity of treatment options and potentially serious consequences of ICDs in PD, it is critical for patients to be monitored closely for their development. As empirically validated treatments for ICDs emerge, it will also be important to examine their efficacy and tolerability in individuals with comorbid PD.

Objective: Our goal was to test the hypothesis that cognitive deficits in Parkinson's disease (PD) are associated with structural and functional changes in the posterior cingulate. To test this hypothesis, we used multi-modal magnetic resonance imaging (MRI) methods including high resolution structural MRI, diffusion tensor imaging (DTI), continuous arterial spin labeling (CASL) perfusion weighted MRI, MRI spectroscopy (MRS), in combination with [18F]-fluorodeoxyglucose positron emission computed tomography (FDG-PET) to assess brain glucose metabolism. Methods: Twenty-nine PD patients (H&Y: 1-3.5) and 23 controls matched for age, gender, and educational level underwent MRI examination, which included structural MRI, DTI, CASL, and MRS. Thirty-four PD (H&Y: 1-3.5) and 20 control subjects underwent FDG-PET. Antiparkinsonian medications were withheld for 12 hours prior to imaging. Pre- and post-processing imaging were analyzed using statistical parametric mapping (SPM). Results: Compared with controls, PD subjects had significantly increased mean diffusivity (MD), reduced N-Acetylaspartate (NAA)/H2O levels, and borderline atrophy in the posterior cingulate. PD patients also had decreased fractional anisotropy (FA) in the white matter below the posterior cingulate and motor cortex, consistent with disrupted microstructure and neuronal loss in PD. Significant metabolic increases on FDG-PET were found in the bilateral posterior cingulate extending to the white matter in PD subjects versus controls. This might potentially represent a compensatory mechanism for structural damage in the adjacent region in PD. The DTI MD, DTI FA, NAA/H2O and glucose metabolism values were all associated with memory decline in PD, as assessed by the California verbal learning test (CVLT). There were no significant cerebral blood flow changes in PD subjects as compared with controls, as assessed by CASL. Together, these findings show evidence for structural damage and functional alterations in the posterior cingulate in PD!

BACKGROUND: : Episodes of subacute worsening of motor function occur commonly in Parkinson disease (PD), but there has been surprisingly little research about the clinical characteristics of these exacerbations in the outpatient setting. METHODS: : Retrospective study of an established cohort of 120 outpatients with PD. Primary outcome measures were the frequency, causes, and outcomes of motor exacerbations. Statistical analysis was performed to compare baseline characteristics of subjects with subsequent exacerbations versus without subsequent exacerbations. RESULTS: : Over an 18-month period, 43 exacerbations occurred, affecting 30 of 120 subjects (25.0%). Infection was the single most frequent underlying cause, accounting for 11 of 43 (25.6%) exacerbations. Other common etiologies were anxiety (n=8), medication errors (n=6), poor adherence (n=6), medication side effects (n=3), and postoperative decline (n=3). Overall, 35 episodes (81.4%) were attributable to reversible or treatable causes. Most subjects recovered fully, but 10 (33.3%) experienced recurrent episodes, 5 (16.7%) suffered permanent decline, and 1 died. At baseline, subjects with exacerbations had a significantly longer median disease duration (7.8 vs. 5.7 y, P=0.003), lower Mini-Mental State Examination scores (27.0+/-3.3 vs. 28.6+/-1.6, P=0.02), higher modified Hoehn and Yahr scores (2.2+/-0.5 vs. 1.9+/-0.5, P=0.006), greater dopaminergic medication use (median, 750.0 vs. 395.0 levodopa equivalents; P=0.009), and a greater prevalence of motor complications (55.2% vs. 29.4%, P=0.01) than subjects without exacerbations. CONCLUSIONS: : Exacerbations are common in PD, associated with more advanced disease, and usually attributable to treatable secondary causes such as intercurrent infection. Increased recognition of these underlying causes may help to decrease morbidity, reduce health care costs, and optimize quality of care in PD.

BACKGROUND: Patient telephone calls are a major form of unreimbursed healthcare utilization in Parkinson's disease (PD), yet little is known about potential risk factors for frequent calling behavior. METHODS: Prospective cohort study of 175 non-demented outpatients with PD. Our primary outcome measure was the frequency of patient telephone calls over a three-month period relative to baseline demographics, State-Trait Anxiety Index (STAI) and Beck Anxiety Inventory (BAI) scores, Unified Parkinson's Disease Rating Scale (UPDRS) motor scores, and medication use. Based on the median call rate (1 call/3 months), subjects were dichotomized into frequent (>/=2 calls) and infrequent (/=55; adjusted OR = 2.62, p = 0.02), sleep disorders (adjusted OR = 2.36, p = 0.02), dyskinesias (adjusted OR = 3.07, p = 0.03), and dopamine agonist use (adjusted OR = 2.27, p = 0.03). Baseline demographics, UPDRS motor scores, and levodopa use were similar in both groups. CONCLUSIONS: Frequent patient telephone calls in PD are independently associated with anxiety, sleep disorders, dyskinesias, and dopamine agonist use, with a minority of patients accounting for the majority of calls. Aggressive treatment of these non-motor symptoms and motor complications might potentially reduce the burden of patient telephone calls in PD.

Outpatient pharmacy errors are common, but little is known about their occurrence in Parkinson's disease (PD). We prospectively studied carbidopa/levodopa pharmacy errors in a cohort of PD outpatients. Over 1 year, pharmacy errors occurred in 8/73 (11%) subjects treated with this medication, producing adverse drug events (ADEs) in 7/8 (87.5%) and increased healthcare utilization in 6/8 (75%) cases. The most common errors were substitution of controlled-release for immediate-release carbidopa/levodopa 25/100 mg (5/8; 62.5%) or dispensation of the wrong carbidopa/levodopa dosage (2/8; 25%). All errors involved ongoing prescriptions, including three interpharmacy transfers. Three subjects (37.5%) questioned pharmacy staff about the change in appearance of the tablets, but the error was corrected in only 1/3 of these cases. Carbidopa/levodopa outpatient pharmacy errors are a common, preventable cause of morbidity and excessive healthcare utilization in PD. Education of healthcare providers, patients, and pharmacy staff is warranted to reduce these errors and associated ADEs.