Introduction: The 2-year Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability (FINGER) multidomain lifestyle intervention trial (NCT01041989) demonstrated beneficial ...

Multidomain lifestyle intervention benefits a large elderly population at risk for cognitive decline and dementia regardless of baseline characteristics: The FINGER trial

In early 1920s, tyramine oxidase was discovered that metabolized tyramine and in 1933 Blaschko demonstrated that this enzyme also metabolized adrenaline, noradrenaline and dopamine. Zeller gave it the name monoamine oxidase (MAO) to distinguish it from the enzyme that oxidatively deaminated diamines. MAO was recognized as an enzyme of crucial interest to pharmacologists because it catalyzed the major inactivation pathway for the catecholamines (and, later, 5-hydroxytryptamine, as well). Within the few decade, the inhibitors of MAO were discovered and introduced for the treatment of depressive illness which was established clinically. However, the first clinical use exposed serious side effects, pharmacological interest in, and investigation of, MAO continued, resulting in the characterization of two forms, distinct forms, MAO-A and -B, and selective inhibitors for them. Selective inhibitors of MAO-B (selegiline, rasagiline and safinamide) have found a therapeutic role in the treatment of Parkinson's disease and reversible inhibitors of MAO-A offered antidepressant activity without the serious side effects of the earlier nonselective MAO inhibitors. Subsequent molecular pharmacological have also generated the concept of neuroprotection, reflecting the possibility of slowing, halting and maybe reversing, neurodegeneration in Parkinson's or Alzheimer's diseases. Increased levels of oxidative stress through the accumulation of iron in the Parkinsonian and Alzheimer brains has been suggested to be critical for the initiation and progress of neurodegeneration. Selective inhibition of brain MAO could contribute importantly to lowering such stress, preventing the formation of hydrogen peroxide. Interaction of Iron with hydrogen peroxide and lead to Fenton reaction and production of the most reactive radical, namely hydroxyl radical. There are complex interactions between free iron levels in brain and MAO, and cascade of neurotoxic events may have practical outcomes for depressive disorders and neurodegenerative diseases. As consequence recent novel therapeutic drugs for neurodegenerative diseases has led to the development of multi target drugs, that possess selective brain MAO A and B inhibitory moiety, iron chelating and antioxidant activities and the ability to increase brain levels of endogenous neurotrophins, such as BDNF, GDNF VEGF and erythropoietin and induce mitochondrial biogenesis.

Monoamine oxidase inhibitors, and iron chelators in depressive illness and neurodegenerative diseases

Safinamide (Xadago®) is an orally active, selective, reversible monoamine oxidase-B inhibitor with both dopaminergic and non-dopaminergic (glutamatergic) properties. In the EU, safinamide is approved for the treatment of mid- to late-stage fluctuating Parkinson’s disease (PD) as add-on therapy to a stable dose of levodopa alone or in combination with other PD medications. Safinamide 50–100 mg/day administered as a fixed or flexible dose significantly increased daily ‘on’ time without dyskinesia (primary endpoint) in patients with mid- to late-stage PD with motor fluctuations in 24-week, placebo-controlled clinical trials. Other outcomes, including motor function, overall clinical status and health-related quality of life, were also generally improved with safinamide. Furthermore, in an 18-month extension of one study, although dyskinesia (primary endpoint) was not significantly improved with safinamide relative to placebo, treatment benefits in other outcomes were generally sustained over 24 months of treatment. Safinamide was generally well tolerated in clinical trials; dyskinesia was the most common adverse event. Although further studies are needed, including comparative and long-term studies, current evidence indicates that safinamide extends the treatment options available for use as add-on therapy to levodopa and other PD medications in patients with mid- to late-stage PD experiencing motor fluctuations.

Safinamide: A Review in Parkinson's Disease.

Strengths and Weaknesses

BACKGROUND: Quality of life in Parkinson's disease (PD) is affected by motor and nonmotor symptoms, necessitating an integrated care approach Existing care models vary considerably in numerous domains The objectives of this study were to perform a systematic review and meta-analysis of PD integrated care models and develop recommendations for a representative model METHODS: We conducted a systematic review of published integrated care models and a meta-analysis of randomized, controlled trials examining integrated care versus standard care The primary outcome was health-related quality of life using a validated PD scale We evaluated levels of care integration using the Rainbow Model of Integrated Care RESULTS: Forty-eight publications were identified, including 8 randomized, controlled trials with health-related quality of life data (n = 1,149 total PD patients) Qualitative evaluation of individual care model integration guided by the Rainbow Model of Integrated Care revealed frequent clinical and professional integration, but infrequent organizational and population-based integration elements Meta-analysis of randomized, controlled trials revealed significant heterogeneity (I(2)  = 90%, P < 00001) Subgroup analysis including only outpatient care models (n = 5) indicated homogeneity of effects (I(2)  = 0%, P = 052) and improved health-related quality of life favoring integrated care, with a small effect size (standardized mean difference [SMD], -017; 95% CI, -031 to -003; P = 002) CONCLUSIONS: Outpatient integrated PD care models may improve patient-reported health-related quality of life compared with standard care; however, because of variable methodological approaches and a high risk of bias related to inherent difficulties in study design (eg, blinding of participants and interventionists), generalizability of these results are difficult to establish The Rainbow Model of Integrated Care is a promising method of evaluating elements and levels of integration from individual patient care to population health in a PD context © 2020 The Authors Movement Disorders published by Wiley Periodicals, LLC on behalf of International Parkinson and Movement Disorder Society

https://movementdisorders.onlinelibrary.wiley.com/doi/pdf/10.1002/mds.28097

Integrated Care in Parkinson's Disease: A Systematic Review and Meta-Analysis.

Safinamide (Xadago®) is a novel medication with both dopaminergic and non-dopaminergic effects, approved first by the European Commission and more recently by the US Food and Drug Administration (FDA) as an adjunctive treatment to carbidopa/levodopa in patients with mid- to late-stage Parkinson's disease (PD) and motor fluctuations. It works through multiple mechanisms, namely as a reversible selective monoamine oxidase-B inhibitor and through modulation of glutamate release. Safinamide is extensively metabolized via oxidation to several inactive metabolites that are excreted primarily through the urine. Several large Phase III clinical trials of patients with advanced PD with motor fluctuations have shown that safinamide, administered orally at doses of 50-100 mg daily, increased ON time with no or non-troublesome dyskinesia, decreased daily OFF time, improved overall motor function (as measured by Unified Parkinson's Disease Rating Scale [UPDRS] part III total score), and quality of life (as measured by Clinical Global Impression-Change and 39-item Parkinson's Disease Questionnaire). In large clinical trials of patients with early PD on a single dopamine agonist, safinamide administered orally at a dose of 100 mg daily improved overall motor function as measured by UPDRS part III total score; however, some of the results reported were exploratory. Safinamide is generally well-tolerated and safe, with few to no treatment-related adverse events. Safinamide does not cause new or worsening dyskinesia and may be able to reduce this symptom in patients reporting it at baseline. Evidence suggests that safinamide is a good option for add-on therapy to carbidopa/levodopa in patients with advanced PD with motor complications, but there is still insufficient evidence to recommend it as monotherapy or add-on therapy in patients with early PD.

/pdf/safinamide-in-the-management-of-patients-with-parkinson-s-1cddtthrt5.pdf

Safinamide in the management of patients with Parkinson’s disease not stabilized on levodopa: A review of the current clinical evidence

OBJECTIVES This study sought to determine whether there is a gender disparity in patients undergoing deep brain stimulation (DBS) surgery for Parkinson's disease (PD) at a single health system, and better understand the reasons for this discrepancy. MATERIALS AND METHODS We analyzed data from the University of Miami DBS Database, which included 3251 PD patients, using chi-square, repeated measures ANOVA, and t tests to examine gender differences in the number of patients referred for surgery, reasons for referral, number receiving/not receiving surgery, reasons for not receiving surgery, and postsurgical outcomes. RESULTS During the study period, 207 PD patients were referred for DBS (75.8% male), and 100 underwent surgery (77.0% male). Of those who did not receive surgery, the most common reasons were need for further medical optimization (26.2%), suboptimal performance on neuropsychological evaluation (22.4%), other reason (20.6%), lost to follow-up (18.7%), or patient preference (12.2%). However, in women one of the most common reasons was patient preference (28.0%), and this was significant compared to men (p < 0.001). Men were more likely to be lost to follow-up (p = 0.046). There was no statistically significant difference in postsurgical outcomes. CONCLUSIONS Despite similar postsurgical improvements, women were less likely to undergo DBS surgery due to their own preference, while men were more likely to be lost to follow-up. These data underscore the need for increased education and awareness of DBS so that all patients with PD who qualify for surgery can benefit from this procedure.

Gender Disparities in Deep Brain Stimulation for Parkinson's Disease

BACKGROUND Randomized clinical trials (RCTs) in Parkinson's disease (PD) have historically enrolled a low number of underrepresented minorities, lessening the generalizability of therapeutic developments. Although there are racial disparities in PD, little is known regarding neuropsychiatric symptoms and other nonmotor manifestations across all races/ethnicities. OBJECTIVE To assess minority participation in PD trials evaluating the treatment of neuropsychiatric symptoms and explore underlying reasons. METHODS We systematically searched PubMed and Embase for RCTs with a primary goal of treating neuropsychiatric symptoms in PD patients from 2000-2019. The pooled prevalence and 95% confidence interval (CI) of being white and enrolled in a clinical trial was calculated using the inverse variance method. I-square was calculated as a measure of heterogeneity and meta-regression was used to evaluate temporal trends. RESULTS We included 63 RCTs with a total of 7,973 patients. In pooled analysis, 11 (17.5%) RCTs reported race/ethnicity. Of studies reporting this data, 5 African American (0.2%), 16 Hispanics (0.64%), and 539 Asians (21.44%) were enrolled. The pooled prevalence of being white in clinical trials was 98% (CI 0.97-0.98, p < 0.001), with 1,908 patients (75.8%). NIH-funded studies were most likely to report racial data when compared to non-NIH trials (p = 0.032). CONCLUSION This large pooled analysis found a small percentage of RCTs reporting race/ethnicity when evaluating treatment of neuropsychiatric symptoms in PD. There was a disproportionally high number of white patients when compared to African Americans and Hispanics. More studies are needed to investigate this discrepancy and improve rates of & minority enrollment in PD trials.

Minority Enrollment in Parkinson's Disease Clinical Trials: Meta-Analysis and Systematic Review of Studies Evaluating Treatment of Neuropsychiatric Symptoms.

Trends of Inpatient Palliative Care Use Among Hospitalized Patients With Parkinson's Disease

Perivascular spaces (PVSs) or Virchow-Robin spaces are spaces filled with interstitial fluid that surround the perforating brain arteries. PVSs are microscopic but visible on MRI when enlarged. They are commonly present on brain MRIs in healthy adults and can be seen in the basal ganglia (BG) and in the area of the substantia innominata at the level of the anterior commissure in up to 60% of individuals. Although the exact role of PVSs is not entirely understood, they are involved in the physiological drainage of interstitial fluid into perivascular and subarachnoid space as well as in the glymphatic drainage systems. PVSs are heterogeneous and differ anatomically and physiologically. PVSs in the basal ganglia (BG-PVSs) are anatomically distinct from cortical PVSs. BG-PVSs dilate to form lacunes and rarely accumulate beta-amyloid, whereas in the cortex, lacunes are rare, but amyloid angiopathy is quite common. Enlarged PVSs are associated with aging, vascular risk factors, vascular diseases, and vascular cognitive impairment and a host of neurodegenerative disorders. However, little is known about PVSs in Parkinson’ disease (PD). There have been sparse reports on brain imaging biomarkers of small-vessel disease in PD, relating periventricular white-matter hyperintensities (WMHs), brain atrophy, and enlarged PVSs in the BG tomotor and cognitive impairments in PD. However, the validation of these observations is lacking, and the mechanisms by which enlarged PVSs negatively affect motor and cognitive changes in PD remain largely unknown. Therefore, the article by Park et al published in this issue of Movement Disorders is a welcoming contribution to the growing literature on the potential vascular promoters of the motor and cognitive decline in PD. In this study, Park et al sought to investigate the presence of PVSs as a risk factor for the development of cognitive decline in PD patients. This was a retrospective study of 271 consecutive PD patients who were followed at the Yonsei University Parkinson Center, Seoul, Korea. The patients were initially divided into 2 groups based on their level of cognition as determined by the results of neuropsychological evaluation at the time of PD diagnosis. Of the total sample, 106 patients had intact cognition (IC), and 156 had mild cognitive impairment (MCI). The patients were all followed for an average of 5.0 2.3 years when cognition was reassessed. The patients were then reclassified based on whether their cognition had declined; 18 of those with previously IC (17%) declined to MCI, and 34 of those with previously diagnosed MCI (22%) declined to dementia. The investigators then analyzed the presence of various risk factors for cognitive decline between the 2 groups. They reported the presence of BG-PVSs and WHM severity on MRI (determined based on STRIVE criteria, assessed by 2 experienced neuroradiologists blinded to the patients’ clinical status), higher levodopa-equivalent dose, hypertension, and lower MiniMental State Examination (MMSE) scores to be independent predictors of greater cognitive decline. On subgroup analysis in the initially IC group, higher BG-PVS severity, hypertension, and depression were associated with cognitive decline. In the group who started with MCI, higher BG-PVS, WHM severity, and lower initial MMSE scores predicted cognitive decline. In discussion of their results, the authors called attention to previous studies that associated BG-PVSs with hypertensive angiopathy and vascular cognitive impairment and suggested that hypertension likely plays a critical role in the pathogenesis of cognitive decline in some proportion of PD patients. With the results reported by Park et al, enlarged BGPVSs on MRI can be added to a growing list of potential biomarkers for cognitive decline in patients with PD (see Fig. 1). In newly diagnosed patients, the DeNoPa study identified diabetes mellitus, hypertension, increased C-reactive protein, higher serum uric acid levels, elevated periodic limbmovement index during sleep, and decreased hippocampal volume on MRI as predictors of cognitive decline. Interestingly, in PD patients, lower CSF *Correspondence to: Tatjana Rundek, MD, PhD, Department of Neurology, The Evelyn F. McKnight Brain Institute, University of Miami Miller School of Medicine, 1120 NW 12th Street, CRB-1348, Miami, FL 33136; E-mail: trundek@med.miami.edu

Danielle S. Shpiner

Papers

Safinamide in the management of patients with Parkinson’s disease not stabilized on levodopa: A review of the current clinical evidence

Gender Disparities in Deep Brain Stimulation for Parkinson's Disease

Minority Enrollment in Parkinson's Disease Clinical Trials: Meta-Analysis and Systematic Review of Studies Evaluating Treatment of Neuropsychiatric Symptoms.

Trends of Inpatient Palliative Care Use Among Hospitalized Patients With Parkinson's Disease

Perivascular spaces in basal ganglia - An innocent bystander in Parkinson's disease?