Introduction: Apomorphine is used to treat OFF periods in Parkinson's disease (PD) patients. AZ-009 is a novel apomorphine formulation that delivers a thermally-generated aerosol to the deep lung... Show moreIntroduction: Apomorphine is used to treat OFF periods in Parkinson's disease (PD) patients. AZ-009 is a novel apomorphine formulation that delivers a thermally-generated aerosol to the deep lung via inhalation with a single breath.Methods: Part A was a randomized, placebo-controlled, double-blind study investigating the safety and pharmacokinetics of multiple ascending doses of AZ-009. PD patients (n = 24) received placebo or 2, 3 or 4 mg AZ-009 once daily for 5 days, followed by three times daily for 2 days with 2 h between doses. Part B was a double-blind crossover study in 8 PD patients who experience OFF periods. During an OFF state, patients received 4 mg AZ-009 and placebo on two consecutive days in a randomized order. MDS-UPDRS III and ON/OFF state were assessed pre- and post-dose.Results: Three times daily dosing with 2, 3 and 4 mg AZ-009 was relatively well tolerated with no apparent accumulation or changes in safety profile. Mild and transient throat irritation and cough were reported most often. AZ-009 was rapidly absorbed with median T-max between 1 and 2 min. When corrected for placebo response, the maximum effect of 4 mg AZ-009 based on MDS-UPDRS III scores was observed at 10 and 30 min post-dose with mean (SD) reductions of 6.8 (9.4) and 6.1 (9.1) points respectively. Whereas 0% of patients turned ON after placebo, 50% turned ON 10 min after 4 mg AZ-009 treatment.Conclusion: AZ-009 is rapidly systemically absorbed and safe to dose three times daily. AZ-009 could provide a faster-acting and easier to use formulation than currently available therapies. Show less
Zwaan, K.F. van der; Mentink, M.D.C.; Jacobs, M.; Roos, R.A.C.; Bot, S.T. de 2022
Huntington's disease (HD) is an inherited neurodegenerative disease. People at risk for HD can choose to get predictive testing years before the clinical onset. HD is characterized by motor,... Show moreHuntington's disease (HD) is an inherited neurodegenerative disease. People at risk for HD can choose to get predictive testing years before the clinical onset. HD is characterized by motor, cognitive and psychiatric symptoms and has a mean age at onset between 30 and 50 years, an age at which people are usually still working. This systematic review focuses on summarizing which disease-specific characteristics influence employment and working capacity in HD.Twenty-three studies were identified and showed that while employment and working capacity in HD are negatively influenced by cognitive decline and motor impairments, apathy already plays a role in the prodromal stage. Moreover, the influence of HD transcends the clinical manifestation of the disease, as some people at risk are already experiencing the impact of HD on employment through fear of or actual genetic discrimination. Employment and working capacity are not influenced by predictive testing for HD in and of itself. Show less
Zitman, F.M.P.; Janssen, A.; Gaag, N.A. van der; Hoffmann, C.F.E.; Zutt, R.; Contarino, M.F. 2021
Introduction: Directional deep brain stimulation (DBS) and pulse with <60 mu s increase side-effects threshold, enlarging the therapeutic window. However, new systems allowing these advanced... Show moreIntroduction: Directional deep brain stimulation (DBS) and pulse with <60 mu s increase side-effects threshold, enlarging the therapeutic window. However, new systems allowing these advanced features are more expensive and often available only for a limited number of patients in some centers. It is unknown how many and which DBS patients actually need the advanced features because of an insufficient improvement with standard parameters. Methods: We included in the analysis all patients with Parkinson's disease, dystonia and tremor who were selected to receive implantation of advanced DBS systems based on specific preoperative or intraoperative clinical features. Results: After a median follow-up of 15 months, 54.9% of the 51 patients implanted with directional leads were using the advanced features in one or both leads (n = 42 leads, 42%), meaning these leads were programmed either with directional stimulation (n = 9, 9%), a shorter pw (n = 20, 20%) or both (n = 13, 13%). This included 92% of patients implanted in the Vim, 44% of those implanted in the STN, and 40% of those implanted in the GPi. Conclusions: DBS systems with advanced features may be particularly indicated for selected patients based on some clinical characteristics and the chosen target. This data may help clinicians allocate resources in a more informed way. Show less
Sprenger, G.P.; Roos, R.A.C.; Zwet, E. van; Reijntjes, R.H.; Achterberg, W.P.; Bot, S.T. de 2021
Introduction: Pain could be an unknown non-motor symptom in Huntington's Disease (HD). The aim is therefore, to study the prevalence of pain interference, painful conditions and analgesic use... Show moreIntroduction: Pain could be an unknown non-motor symptom in Huntington's Disease (HD). The aim is therefore, to study the prevalence of pain interference, painful conditions and analgesic use across the different stages of HD and compare these levels to non-HD gene mutation carriers.Methods: A cross-sectional analysis of the Enroll-HD study was conducted in premanifest, manifest HD gene mutation carriers (n = 3989 and n = 7,485, respectively) and in non-HD gene mutation carriers (n = 3719). To investigate group differences, multivariable logistic regression analysis was performed with pairwise comparisons.Results: In the HD mutation carriers, the overall prevalence of pain interference was 34% (95% CI 31%-35%), of painful conditions 17% (95% CI 15%-19%) and analgesic use 13% (95% CI 11%-15%). Compared to non-mutation carriers, the prevalence of pain interference was significantly higher in the middle stage of HD (33% [95% CI 31%-35%] vs 42% [95% CI 39%-45%], P = 0,02), whereas the prevalence of painful conditions was significant lower in the late and middle stage of HD (17% [95% CI 16%-18%] vs 12% [95% CI 10%-14%], 15% [95% CI 13%-17%], P < 0,01]. No significant group difference was present in analgesic use.Conclusions: The prevalence of pain interference increases as HD progresses, however, the prevalence of painful conditions and analgesics do not increase accordingly. Further studies are necessary to investigate the aetiology of pain in HD and the risk for undertreatment of pain. Show less
Sprenger, G.P.; Roos, R.A.C.; Zwet, E. van; Reijntjes, R.H.; Achterberg, W.P.; Bot, S.T. de 2021
Introduction: Pain could be an unknown non-motor symptom in Huntington's Disease (HD). The aim is therefore, to study the prevalence of pain interference, painful conditions and analgesic use... Show moreIntroduction: Pain could be an unknown non-motor symptom in Huntington's Disease (HD). The aim is therefore, to study the prevalence of pain interference, painful conditions and analgesic use across the different stages of HD and compare these levels to non-HD gene mutation carriers.Methods: A cross-sectional analysis of the Enroll-HD study was conducted in premanifest, manifest HD gene mutation carriers (n = 3989 and n = 7,485, respectively) and in non-HD gene mutation carriers (n = 3719). To investigate group differences, multivariable logistic regression analysis was performed with pairwise comparisons.Results: In the HD mutation carriers, the overall prevalence of pain interference was 34% (95% CI 31%-35%), of painful conditions 17% (95% CI 15%-19%) and analgesic use 13% (95% CI 11%-15%). Compared to non-mutation carriers, the prevalence of pain interference was significantly higher in the middle stage of HD (33% [95% CI 31%-35%] vs 42% [95% CI 39%-45%], P = 0,02), whereas the prevalence of painful conditions was significant lower in the late and middle stage of HD (17% [95% CI 16%-18%] vs 12% [95% CI 10%-14%], 15% [95% CI 13%-17%], P < 0,01]. No significant group difference was present in analgesic use.Conclusions: The prevalence of pain interference increases as HD progresses, however, the prevalence of painful conditions and analgesics do not increase accordingly. Further studies are necessary to investigate the aetiology of pain in HD and the risk for undertreatment of pain. Show less
Akhoundi, F.H.; Contarino, M.F.; Fasano, A.; Vaidyanathan, J.; Ziaee, M.; Tabatabaee, S.N.; Rohani, M. 2021
As the number of patients implanted with deep brain stimulation systems increases, coexistence with cardiac implantable electronic devices (CIEDs) poses questions about safety. We systematically... Show moreAs the number of patients implanted with deep brain stimulation systems increases, coexistence with cardiac implantable electronic devices (CIEDs) poses questions about safety. We systematically reviewed the literature on coexisting DBS and CIED. Eighteen reports of 34 patients were included. Device-device interactions were reported in 6 patients. Sources of complications were extensively reviewed and cautious measures which could be considered as part of a standard checklist for careful consideration are suggested. Show less
Background: Caregivers of patients with Parkinson's Disease (PD) often provide important support in the preand postoperative phase of Deep Brain Stimulation (DBS). DBS-associated changes of patient... Show moreBackground: Caregivers of patients with Parkinson's Disease (PD) often provide important support in the preand postoperative phase of Deep Brain Stimulation (DBS). DBS-associated changes of patient-functioning may affect caregiver wellbeing and impact the support system. Factors influencing caregiver-wellbeing under these circumstances are incompletely known.Objective: to systematically review studies of sufficient methodological quality on the impact of DBS on caregivers of PD patients.Methods: using PRISMA guidelines, major databases were searched up to May 2020. Five subcategories were identified: Caregiver burden, Caregiver cognitive and psychiatric functioning, Caregiver Quality of Life (QoL), Marital Satisfaction/Conflicts, and Caregiver Satisfaction. Quality was assessed using an in-house checklist.Results: 293 studies were identified; 12 were ultimately included. Caregiver burden, psychiatric and cognitive functioning and QoL remained relatively unchanged. Results on marital satisfaction/conflicts were contrasting: an increase in marital conflicts despite improved relationship quality scores DBS. Caregiver satisfaction with surgery was low with 50-58% of caregivers being disappointed with DBS outcomes. Concerning caregiver related factors: a higher preoperative caregiver QoL, younger age, lower scores on psychiatric rating scales, and more favourable preoperative relationship quality scores, were associated with better caregiver wellbeing. A favourable patient-profile includes younger age and age-at-onset, shorter disease duration, lower medication requirements, and lower scores on psychiatric rating scales.Conclusion: Although most patient- and caregiver-related subdomains remained unchanged after DBS, dissatisfaction among caregivers and marital problems may constitute a large risk for a well-functioning patient-caregiver dyad. Early recognition of potential problem situations may improve post-DBS care for both patients and caregivers. Show less
Parkinson's disease (PD) is a multifactorial disorder with complex etiology. The most prevalent PD associated mutation, LRRK2-G2019S is linked to familial and sporadic cases. Based on the multitude... Show moreParkinson's disease (PD) is a multifactorial disorder with complex etiology. The most prevalent PD associated mutation, LRRK2-G2019S is linked to familial and sporadic cases. Based on the multitude of genetic predispositions in PD and the incomplete penetrance of LRRK2-G2019S, we hypothesize that modifiers in the patients' genetic background act as susceptibility factors for developing PD. To assess LRRK2-G2019S modifiers, we used human induced pluripotent stem cell-derived neuroepithelial stem cells (NESCs). Isogenic controls distinguish between LRRK2-G2019S dependent and independent cellular phenotypes. LRRK2-G2019S patient and healthy mutagenized lines showed altered NESC self-renewal and viability, as well as impaired serine metabolism. In patient cells, phenotypes were only partly LRRK2-G2019S dependent, suggesting a significant contribution of the genetic background. In this context we identified the gene serine racemase (SRR) as a novel patient-specific, developmental, genetic modifier contributing to the aberrant phenotypes. Its enzymatic product, n-serine, rescued altered cellular phenotypes. Susceptibility factors in the genetic background, such as SRR, could be new targets for early PD diagnosis and treatment. Show less
