Sex Differences in Parkinson's Disease: From Bench to Bedside.

BACKGROUND: Parkinson's disease (PD) is the second most common neurodegenerative disorder after Alzheimer's disease and gender differences have been described on several aspects of PD. In the present commentary, we aimed to collect and discuss the currently available evidence on gender differences in PD regarding biomarkers, genetic factors, motor and non-motor symptoms, therapeutic management (including pharmacological and surgical treatment) as well as preclinical studies. METHODS: A systematic literature review was performed by searching the Pubmed and Scopus databases with the search strings "biomarkers", "deep brain stimulation", "female", "gender", "genetic", "levodopa", "men", "male", "motor symptoms", "non-motor symptoms", "Parkinson disease", "sex", "surgery", and "women". RESULTS: The present review confirms the existence of differences between men and women in Parkinson Disease, pointing out new information regarding evidence from animal models, genetic factors, biomarkers, clinical features and pharmacological and surgical treatment. CONCLUSIONS: The overall goal is to acquire new informations about sex and gender differences in Parkinson Disease, in order to develop tailored intervetions.

Cutaneous sensory and autonomic denervation in progressive supranuclear palsy.

AIM: Progressive Supranuclear Palsy (PSP) is a progressive neurodegenerative tauopathy characterised by motor, behavioural and cognitive dysfunction. While in the last decade, sensory and autonomic disturbances as well as peripheral nerve involvement are well-recognised in Parkinson's Disease (PD), little is known in this regard for PSP. Herein, we aim to assess peripheral sensory and autonomic nerve involvement in PSP and to characterise possible differences in morpho-functional pattern compared to PD patients. METHODS: We studied 27 PSP and 33 PD patients without electrophysiological signs of neuropathy, and 33 healthy controls (HC). In addition to motor impairment, evaluated by means of UPDRS-III and the PSP rating scale, all patients underwent clinical, functional and morphological assessment of sensory-autonomic nerves through dedicated questionnaires, sympathetic skin response, dynamic sweat test and skin biopsies. The analysis of cutaneous sensory and autonomic innervation was performed using indirect immunofluorescence and confocal microscopy. RESULTS: PSP patients displayed a length-dependent loss of sensory and autonomic nerve fibres associated with functional impairment compared to HC and, overall, a more severe picture than in PD patients. The disease severity correlated with the loss of intraepidermal nerve fibre density in the leg of PSP patients (p < 0.05). CONCLUSION: We demonstrated a length-dependent small fibre pathology in PSP, more severe compared to PD, and paralleling disease severity. Our findings suggest the morphological and functional study of cutaneous nerves as possible biomarkers to monitor disease progression and response to new treatments.

Levodopa Versus Dopamine Agonist after Subthalamic Stimulation in Parkinson's Disease.

BACKGROUND: No clinical trials have been specifically designed to compare medical treatments after surgery in Parkinson's disease (PD). OBJECTIVE: Study's objective was to compare the efficacy and safety of levodopa versus dopamine agonist monotherapy after deep brain stimulation (DBS) in PD. METHODS: Thirty-five surgical candidates were randomly assigned to receive postoperative monotherapy with either levodopa or dopamine agonist in a randomized, single-blind study. All patients were reevaluated in short- (3 months), mid- (6 months), and long-term (2.5 years) follow-up after surgery. The primary outcome measure was the change in the Non-Motor Symptoms Scale (NMSS) 3 months after surgery. Secondary outcome measures were the percentage of patients maintaining monotherapy, change in motor symptoms, and specific non-motor symptoms (NMS). Analysis was performed primarily in the intention-to-treat population. RESULTS: Randomization did not significantly affect the primary outcome (difference in NMSS between treatment groups was 4.88 [95% confidence interval: -11.78-21.53, P = 0.566]). In short- and mid-term follow-up, monotherapy was safe and feasible in more than half of patients (60% in short- and 51.5% in mid-term follow-up), but it was more often possible for patients on levodopa. The ability to maintain dopamine agonist monotherapy was related to optimal contact location. In the long term, levodopa monotherapy was feasible only in a minority of patients (34.2%), whereas dopamine agonist monotherapy was not tolerated due to worsening of motor conditions or occurrence of impulse control disorders. CONCLUSIONS: This trial provides evidence for simplifying pharmacological treatment after functional neurosurgery for PD. The reduction in dopamine receptor agonists should be attempted while monitoring for occurrence of NMSs, such as apathy and sleep disturbances. © 2020 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

The role of disease duration and severity on novel clinical subtypes of Parkinson disease.

INTRODUCTION: One of the latest subtyping systems of Parkinson disease (PD) identifies motor severity, cognitive dysfunction, dysautonomia, and rapid eye movement behavior disorder as key features for phenotyping patients into three different subtypes (i.e., mild motor-predominant, diffuse-malignant and intermediate). Since PD subtypes are clinically most relevant if they are mutually exclusive and consistent over-time, we explored the impact of disease stage and duration on these novel subtypes. METHODS: One-hundred-twenty-two consecutive patients, with a disease duration ranging from 0 to 20 years, were allocated as suggested into these three subtypes. The relationship between either disease duration or stage, as measured by the Hoehn and Yahr staging, and subtype allocation was explored. RESULTS: Significant differences in subtype distribution were observed across patients stratified according to either disease duration or staging, with the diffuse-malignant subtypes increasing in prevalence as the disease advanced. Both disease duration and staging were independent predictors of subtype allocation. CONCLUSIONS: These novel PD subtypes are significantly influenced by disease duration and staging, which might suggest that they do not represent mutually exclusive disease pathways. This should be taken into account when attempting correlations with putative biomarkers of disease progression.

Screening for Aphasia in NeuroDegeneration for the Diagnosis of Patients with Primary Progressive Aphasia: Clinical Validity and Psychometric Properties.

BACKGROUND: We evaluated the psychometric proprieties of the Screening for Aphasia in NeuroDegeneration (SAND) battery in Italian primary progressive aphasia (PPA) and movement disorder (MD) patients. METHODS: The sample included 30 consecutive PPA and 45 MD patients who completed the SAND battery together with a clinical interview and a neurological/neuropsychological examination and 130 healthy controls (HC). RESULTS: The SAND battery showed good internal consistency and good convergent and divergent validity. receiver operating characteristic analysis revealed an area under the curve of 0.978 for PPA versus HC and of 0.786 for PPA versus MD. A cutoff ≥3 gave a sensitivity of 0.933% and a specificity of 0.946% for discriminating PPA versus HC, whereas a cutoff ≥5 gave a sensitivity of 0.767% and a specificity of 0.667% for discriminating PPA versus MD. CONCLUSION: These results indicate that the SAND battery is an adequate, reliable, and valid diagnostic tool for PPA.

Predictors of deep brain stimulation outcome in tremor patients.

BACKGROUND: Deep brain stimulation of the ventro-intermedius nucleus of the thalamus is an established treatment for tremor of differing etiologies but factors that may predict the short- and especially long-term outcome of surgery are still largely unknown. METHODS: We retrospectively investigated the clinical, pharmacological, electrophysiological and anatomical features that might predict the initial response and preservation of benefit in all patients who underwent deep brain stimulation for tremor. Data were collected at the following time points: baseline (preoperative), one-year post-surgery, and most recent visit. Tremor severity was recorded using the Fahn-Tolosa-Marin Tremor Rating Scale and/or the Unified Parkinson's Disease Rating Scale. RESULTS: A total of 52 patients were included in the final analysis: 31 with essential tremor, 15 with cerebellar tremor of different etiologies, and 6 with Parkinson's disease. Long-term success (mean follow-up duration 34.7 months, range 1.7-121.1 months) was reported in 63.5%. Predictors of long-term benefit were: underlying tremor etiology (best outcome in Parkinson's disease, worst outcome in cerebellar tremor); age at surgery (the older the better); baseline tremor severity (the greater the better); lack of response to benzodiazepines; a more anterior electrode placement and single-unit beta power (the greater the better). CONCLUSIONS: Specific patients' features (including single unit beta activity) and electrode locations may predict the short- and long-term benefit of thalamic stimulation for tremor. Future prospective studies enrolling a much larger sample of patients are needed to substantiate the associations detected by this retrospective study.

Medical Management of Movement Disorders.

Pharmacological treatment is the cornerstone in the management of movement disorders. Although most available treatment options have no impact on the underlying process of each movement disorder, symptomatic therapies can significantly improve patient's quality of life and level of disability. Here, we review the current knowledge on clinical symptomatic management of Parkinson's disease (both early and advanced stages), essential tremor, dystonia, and chorea. Ideally, treatment should be carried out by specialists with reasonable experience in movement disorders, as it needs to be tailored for each patient depending on several appraisals, including but not limited to patients' needs, compliance issues, potential side effects, caregiver support, and presence of comorbidities. When medications fail to improve patient's disability, stereotactic surgery is a well-established option for most of these disorders.

The SAC1 domain in synaptojanin is required for autophagosome maturation at presynaptic terminals.

Presynaptic terminals are metabolically active and accrue damage through continuous vesicle cycling. How synapses locally regulate protein homeostasis is poorly understood. We show that the presynaptic lipid phosphatase synaptojanin is required for macroautophagy, and this role is inhibited by the Parkinson's disease mutation R258Q. Synaptojanin drives synaptic endocytosis by dephosphorylating PI(4,5)P2, but this function appears normal in SynaptojaninRQ knock-in flies. Instead, R258Q affects the synaptojanin SAC1 domain that dephosphorylates PI(3)P and PI(3,5)P2, two lipids found in autophagosomal membranes. Using advanced imaging, we show that SynaptojaninRQ mutants accumulate the PI(3)P/PI(3,5)P2-binding protein Atg18a on nascent synaptic autophagosomes, blocking autophagosome maturation at fly synapses and in neurites of human patient induced pluripotent stem cell-derived neurons. Additionally, we observe neurodegeneration, including dopaminergic neuron loss, in SynaptojaninRQ flies. Thus, synaptojanin is essential for macroautophagy within presynaptic terminals, coupling protein turnover with synaptic vesicle cycling and linking presynaptic-specific autophagy defects to Parkinson's disease.

Exploring risk factors for stuttering development in Parkinson disease after deep brain stimulation.

BACKGROUND: Stuttering is a speech disorder with disruption of verbal fluency, occasionally present in Parkinson's disease (PD). PD co-incident stuttering may either worsen or improve after Deep Brain Stimulation (DBS). METHODS: Sixteen out of 453 PD patients (3.5%) exhibited stuttering after DBS (PD-S) and were compared with a group of patients without stuttering (PD-NS) using non-parametric statistics. RESULTS: After DBS, stuttering worsened in 3 out of 4 patients with co-incidental stuttering. Most PD-S underwent subthalamic (STN) DBS, but 4 were implanted in the globus pallidus (GPi). Nine out of 16 PD-S (56.3%) reported a positive familial history for stuttering compared to none of the PD-NS. PD-S were mainly male (81.3%) with slight worse motor features compared to PD-NS. CONCLUSION: Herein, we describe a group of PD patients developing stuttering after DBS and report the presence of a positive familial history for stuttering as the most relevant risk factor, suggesting a possible underlying genetic cause. The fact that stuttering occurred after either STN or GPi DBS is an argument against the impact of medication reduction on stuttering.

The relevance of gender in Parkinson's disease: a review.

Since the official and systematic inclusion of sex and gender in biomedical research, gender differences have been acknowledged as important determinants of both the susceptibility to develop neurodegenerative diseases in general population and the clinical and therapeutic management of neurodegenerative patients. In this review, we gathered the available evidence on gender differences in Parkinson's disease (PD) regarding clinical phenotype (including motor and non-motor symptoms), biomarkers, genetics and therapeutic management (including pharmacological and surgical treatment). Finally, we will briefly discuss the role of estrogens in determining such differences. Several data demonstrate that PD in women starts with a more benign phenotype, likely due to the effect of estrogens. However, as the disease progresses, women are at higher risk of developing highly disabling treatment-related complications, such as motor and non-motor fluctuations as well as dyskinesia, compared with men. In addition, women have lower chances of receiving effective treatment for PD as deep brain stimulation. Taken together these findings challenge the definition of a more benign phenotype in women. Still, much work needs to be done to better understand the interaction between gender, genetics and environmental factors in determining the PD risk and clinical features. Improving our understanding in this field may result in implementation of strategies to identify prodromal PD and speed efforts to discern new directions for disease tailored treatment and management.

Deep Brain Stimulation Target Selection for Parkinson's Disease.

During the "DBS Canada Day" symposium held in Toronto July 4-5, 2014, the scientific committee invited experts to discuss three main questions on target selection for deep brain stimulation (DBS) of patients with Parkinson's disease (PD). First, is the subthalamic nucleus (STN) or the globus pallidus internus (GPi) the ideal target? In summary, both targets are equally effective in improving the motor symptoms of PD. STN allows a greater medications reduction, while GPi exerts a direct antidyskinetic effect. Second, are there further potential targets? Ventral intermediate nucleus DBS has significant long-term benefit for tremor control but insufficiently addresses other motor features of PD. DBS in the posterior subthalamic area also reduces tremor. The pedunculopontine nucleus remains an investigational target. Third, should DBS for PD be performed unilaterally, bilaterally or staged? Unilateral STN DBS can be proposed to asymmetric patients. There is no evidence that a staged bilateral approach reduces the incidence of DBS-related adverse events.

Establishing a Standard of Care for Deep Brain Stimulation Centers in Canada.

During the "DBS Canada Day" symposium held in Toronto July 4-5, 2014, the scientific committee invited experts to share their knowledge regarding deep brain stimulation (DBS) management of movement disorders in three domains: (1) the programming algorithms, (2) the necessary team to run a neurosurgery program, and (3) the appropriate scales to better define in a more comprehensive fashion the effect of the brain surgery. Each presentation was followed by an open discussion, and this article reports on the conclusions of this meeting on these three questions. Concerning programming, the role of the pulse width and the switching off of the stimulation at night for thalamic stimulation for the control of tremor have been discussed. The algorithms proposed in the literature for programming in Parkinson's disease (PD) need validation. In dystonia, the use of monopolar vs bipolar parameters, the use of low vs high frequencies and the use of smaller versus larger pulse widths all need to be examined properly. Concerning the necessary team to run a neurosurgical program, recommendations will follow the suggestions for standardized outcome measures. Regarding the outcome measures for DBS in PD, investigations need to focus on the non-motor aspects of PD. Identifying which nonmotor symptoms respond to DBS would allow a better screening before and satisfaction postoperatively. There is an important need for more data to determine the optimal programming protocol and the standard measures that should be performed routinely by all centers.

Caffeine consumption and the 4-year progression of de novo Parkinson's disease.

INTRODUCTION: Higher caffeine consumption has been associated with reduced risk of Parkinson's disease (PD), and with a more benign progression of motor and non-motor symptoms (NMS). The present observational cohort study investigated motor and non-motor correlates of caffeine consumption in de novo PD. METHODS: 79 newly diagnosed, drug naïve PD patients have been included and followed up for 4 years. The total caffeine use was calculated with the Caffeine Consumption Questionnaire. Following study variables were recorded at baseline, and after 2 and 4 years: UPDRS part III, UPDRS part IV, l-dopa Equivalent Daily Dose (LEDD), NMS Questionnaire (NMSQuest), and the time occurring from PD diagnosis to the need for l-dopa treatment. Age, gender and disease duration were included as covariates in the statistical models. RESULTS: The average daily caffeine consumption was 296.1 ± 157.2 mg. At Cox regression models, higher caffeine consumption was associated with a lower rate of starting l-Dopa treatment (HR = 0.630; 95%CI = 0.382-0.996). At the mixed-effects linear regression models considering the whole study period, each additional espresso cup per day (50 mg of caffeine) was more likely associated with 5-point lower UPDRS part III total score (Coef = -0.01; 95%CI = -0.02 to 0.00), with 50% reduced LEDD (Coef = -0.01; 95%CI = -0.15 to 0.00; p = 0.021), and with 5-point lower NMSQuest total score (Coef = -0.01; 95%CI = -0.01 to 0.00), but not with UPDRS part IV total score (Coef = -0.00; 95%CI = -0.00 to 0.00). CONCLUSION: Caffeine consumption was associated with a reduced accrual of motor and non-motor disability during 4-year follow-up in de novo PD, highlighting the rationale for using adenosine A2A antagonists since the early phases of PD.

Eligibility Criteria for Deep Brain Stimulation in Parkinson's Disease, Tremor, and Dystonia.

In this review, the available evidence to guide clinicians regarding eligibility for deep brain stimulation (DBS) in the main conditions in which these forms of therapy are generally indicated-Parkinson's disease (PD), tremor, and dystonia-is presented. In general, the literature shows that DBS is effective for PD, essential tremor, and idiopathic dystonia. In these cases, key points in patient selection must include the level of disability and inability to manage symptoms using the best available medical therapy. Results are, however, still not optimal when dealing with other aetiologies, such as secondary tremors and symptomatic dystonia. Also, in PD, issues such as age and neuropsychiatric profile are still debatable parameters. Overall, currently available literature is able to guide physicians on basic aspects of patient selection and indications for DBS; however, a few points are still debatable and controversial. These issues should be refined and clarified in future studies.

Low-frequency Subthalamic Stimulation in Parkinson's Disease: Long-term Outcome and Predictors.

BACKGROUND: Parkinson's disease patients undergoing subthalamic nucleus deep brain stimulation (STN DBS) at standard frequency (>100 Hz) often develop gait impairment, postural instability and speech difficulties. Low frequency stimulation (<100 Hz, LFS) can improve such axial symptoms, but there are concerns that improvement may be transient. OBJECTIVE: To identify long-term outcome and predictors of low-frequency subthalamic stimulation in Parkinson's disease. METHODS: Through a chart review we identified 85 out of 324 STN DBS patients who received a trial of LFS and describe their characteristics and outcome predictors. RESULTS: Patients were switched to LFS (<100 Hz) 3.8 ± 3.3 years after surgery. Most patients (64%) attained a subjective improvement of gait, speech or balance for 2.0 ± 1.9 years. Motor scores improved within the first year after the stimulation change and showed a slower progression over time when compared to patients switched back to high frequency stimulation. UPDRS III axial score on medication before surgery and the y-axis coordinate of the active contact were independent predictors of LFS retention. CONCLUSIONS: This report provides evidence that the use of LFS yields an enduring benefit in a considerable percentage of patients who develop axial motor symptoms during conventional stimulation.

Programming Deep Brain Stimulation for Tremor and Dystonia: The Toronto Western Hospital Algorithms.

BACKGROUND: Deep brain stimulation (DBS) is an effective treatment for essential tremor (ET) and dystonia. After surgery, a number of extensive programming sessions are performed, mainly relying on neurologist's personal experience as no programming guidelines have been provided so far, with the exception of recommendations provided by groups of experts. Finally, fewer information is available for the management of DBS in ET and dystonia compared with Parkinson's disease. OBJECTIVE/HYPOTHESIS: Our aim is to review the literature on initial and follow-up DBS programming procedures for ET and dystonia and integrate the results with our current practice at Toronto Western Hospital (TWH) to develop standardized DBS programming protocols. METHODS: We conducted a literature search of PubMed from inception to July 2014 with the keywords "balance", "bradykinesia", "deep brain stimulation", "dysarthria", "dystonia", "gait disturbances", "initial programming", "loss of benefit", "micrographia", "speech", "speech difficulties" and "tremor". Seventy-six papers were considered for this review. RESULTS: Based on the literature review and our experience at TWH, we refined three algorithms for management of ET, including: (1) initial programming, (2) management of balance and speech issues and (3) loss of stimulation benefit. We also depicted algorithms for the management of dystonia, including: (1) initial programming and (2) management of stimulation-induced hypokinesia (shuffling gait, micrographia and speech impairment). CONCLUSIONS: We propose five algorithms tailored to an individualized approach to managing ET and dystonia patients with DBS. We encourage the application of these algorithms to supplement current standards of care in established as well as new DBS centers to test the clinical usefulness of these algorithms in supplementing the current standards of care.

Programming Deep Brain Stimulation for Parkinson's Disease: The Toronto Western Hospital Algorithms.

BACKGROUND: Deep brain stimulation (DBS) is an established and effective treatment for Parkinson's disease (PD). After surgery, a number of extensive programming sessions are performed to define the most optimal stimulation parameters. Programming sessions mainly rely only on neurologist's experience. As a result, patients often undergo inconsistent and inefficient stimulation changes, as well as unnecessary visits. OBJECTIVE/HYPOTHESIS: We reviewed the literature on initial and follow-up DBS programming procedures and integrated our current practice at Toronto Western Hospital (TWH) to develop standardized DBS programming protocols. We propose four algorithms including the initial programming and specific algorithms tailored to symptoms experienced by patients following DBS: speech disturbances, stimulation-induced dyskinesia and gait impairment. METHODS: We conducted a literature search of PubMed from inception to July 2014 with the keywords "deep brain stimulation", "festination", "freezing", "initial programming", "Parkinson's disease", "postural instability", "speech disturbances", and "stimulation induced dyskinesia". Seventy papers were considered for this review. RESULTS: Based on the literature review and our experience at TWH, we refined four algorithms for: (1) the initial programming stage, and management of symptoms following DBS, particularly addressing (2) speech disturbances, (3) stimulation-induced dyskinesia, and (4) gait impairment. CONCLUSIONS: We propose four algorithms tailored to an individualized approach to managing symptoms associated with DBS and disease progression in patients with PD. We encourage established as well as new DBS centers to test the clinical usefulness of these algorithms in supplementing the current standards of care.

Recent advances in Essential Tremor: Surgical treatment.

While no real breakthrough in the medical treatment of Essential Tremor (ET) has recently emerged, surgical field is expanding exponentially. Purpose of this review is to examine the recent and future developments of the surgical treatments for ET. Technological advances are shaping the present and the future application of deep brain stimulation (DBS) in ET. New electrode configurations as well as new implantable pulse generators are now available. Application of closed-loop or adaptive stimulation in clinical practice will allow DBS to deliver stimulation in a truly physiological way to restore aberrant neurological circuits on demand, thus avoiding side effects, tolerance and also saving the battery life. Besides DBS and standard thalamotomy, novel surgical approaches for ET are on the horizon. The development of MRI-guided focused ultrasound technique has been the new frontier of deep brain lesional therapies. Although the benefit of motor cortex stimulation is yet to be defined, this minimally invasive approach remains intriguing. Although the advances of surgical treatments along the clinical and technological directions described in this review will certainly contribute to a successful management of ET patients, future studies need to consider critical issues such as the heterogeneity of ET and the development of tolerance.

Non-Motor Correlates of Smoking Habits in de Novo Parkinson's Disease.

BACKGROUND: Parkinson's disease (PD) subjects are less likely to ever smoke and are more prone to quit smoking, as compared to controls. Therefore, smoking habits can be considered part of the non-motor phenotype, preceding the onset of motor PD by several years. OBJECTIVE: To explore non-motor symptom (NMS) correlates of smoking habits in de novo PD. METHODS: This cross-sectional study included 281 newly diagnosed, drug-naïve PD subjects, recruited in Naples (Italy) and in Kassel (Germany). All subjects completed the NMS Questionnaire (NMSQ), and were investigated for smoking status (never, current and former smokers) and intensity (pack-years). RESULTS: 140 PD subjects never smoked, 20 currently smoked, and 121 had quit smoking before PD diagnosis. NMSQ total score did not associate with smoking status, but with smoking intensity (p = 0.028; coefficient = 0.088). A multinomial logistic regression stepwise model presenting never smoking as reference, selected as NMSQ correlates of current smoking: sex difficulties (p = 0.002; OR = 5.254), daytime sleepiness (p = 0.046; OR = 0.085), insomnia (p = 0.025; OR = 0.135), and vivid dreams (p = 0.040; OR = 3.110); and of former smoking: swallowing (p = 0.013; OR = 0.311), nausea (p = 0.027; OR = 7.157), unexplained pains (p = 0.002; OR = 3.409), forgetfulness (p = 0.005; OR = 2.592), sex interest (p = 0.007; OR = 0.221), sex difficulties (p = 0.038; OR = 4.215), and daytime sleepiness (p = 0.05; OR = 0.372). An ordinal logistic regression stepwise model selected as NMSQ correlates of smoking intensity: nocturnal restlessness (p = 0.027; coefficient = 0.974), and leg swelling (p = 0.004; coefficient = 1.305). CONCLUSIONS: Certain NMSs are associated with different smoking status and intensity, suggesting a variety of adaptive mechanisms to cigarette smoking.