Bradykinesia in Neurodegenerative Disorders: A Blinded Video Analysis of Pathology-Proven Cases.

BACKGROUND: Bradykinesia is a cardinal feature in parkinsonisms. No study has assessed the differential features of bradykinesia in patients with pathology-proven synucleinopathies and tauopathies. OBJECTIVE: We examined whether bradykinesia features (speed, amplitude, rhythm, and sequence effect) may differ between pathology-proven synucleinopathies and tauopathies. METHODS: Forty-two cases who underwent autopsy were included and divided into synucleinopathies (Parkinson's disease and dementia with Lewy bodies) and tauopathies (progressive supranuclear palsy). Two raters blinded to the diagnosis retrospectively scored the Movement Disorders Society-Unified Parkinson's Disease Rating Scale Part III and Modified Bradykinesia Rating Scale on standardized videotaped neurological examinations. Bradykinesia scores were compared using the Mann-Whitney test and logistic regression models to adjust for disease duration. RESULTS: Demographic and clinical parameters were similar between synucleinopathies and tauopathies. There were no differences between speed, amplitude, rhythm, and sequence effect in synucleinopathies and tauopathies in unadjusted comparisons and adjusted models (all P > 0.05). CONCLUSIONS: Clinical bradykinesia features do not distinguish the underlying neuropathology in neurodegenerative parkinsonisms. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Does Head Tremor Predict Postural Instability After Bilateral Thalamic Stimulation in Essential Tremor?

Essential tremor (ET) may present with head tremor (HT), of presumed cerebellar nature. Deep brain stimulation (DBS) targeting the ventral intermediate (Vim) nucleus of the thalamus is a highly effective therapy for medication-refractory ET. However, stimulation-related side effects may include cerebellar abnormalities, such as postural instability. This retrospective cohort study evaluated the risk of post-Vim DBS postural instability (primary outcome measure) in patients with versus without head tremor (HT vs. nHT). The primary outcome measure, namely post-DBS postural instability, was assessed in both groups using a Wilcoxon rank sum t-test. The time to postural instability was determined using Cox proportional hazards regression analysis adjusted for age and sex. Out of 30 patients analyzed during the follow up period, there was similar postural instability detected in HT (9/14, 64%) and nHT patients (11/16, 69%) at 24 months post-Vim DBS (p=0.82), adjusted hazard ratio[aHR]=0.82, p=0.69). These data suggest that the presence or absence of HT does not have an impact on postural instability after bilateral Vim DBS in patients with ET.

Oral ENT-01 Targets Enteric Neurons to Treat Constipation in Parkinson Disease : A Randomized Controlled Trial.

BACKGROUND: Parkinson disease (PD) is associated with α-synuclein (αS) aggregation within enteric neurons. ENT-01 inhibits the formation of αS aggregates and improved constipation in an open-label study in patients with PD. OBJECTIVE: To evaluate the safety and efficacy of oral ENT-01 for constipation and neurologic symptoms in patients with PD and constipation. DESIGN: Randomized, placebo-controlled phase 2b study. (ClinicalTrials.gov: NCT03781791). SETTING: Outpatient. PATIENTS: 150 patients with PD and constipation. INTERVENTION: ENT-01 or placebo daily for up to 25 days. After baseline assessment of constipation severity, daily dosing was escalated to the prokinetic dose, the maximum dose (250 mg), or the tolerability limit, followed by a washout period. MEASUREMENTS: The primary efficacy end point was the number of complete spontaneous bowel movements (CSBMs) per week. Neurologic end points included dementia (assessed using the Mini-Mental State Examination [MMSE]) and psychosis (assessed using the Scale for the Assessment of Positive Symptoms adapted for PD [SAPS-PD]). RESULTS: The weekly CSBM rate increased from 0.7 to 3.2 in the ENT-01 group versus 0.7 to 1.2 in the placebo group (P < 0.001). Improvement in secondary end points included SBMs (P = 0.002), stool consistency (P < 0.001), ease of passage (P = 0.006), and laxative use (P = 0.041). In patients with dementia, MMSE scores improved by 3.4 points 6 weeks after treatment in the ENT-01 group (n = 14) versus 2.0 points in the placebo group (n = 14). Among patients with psychosis, SAPS-PD scores improved from 6.5 to 1.7 six weeks after treatment in the ENT-01 group (n = 5) and from 6.3 to 4.4 in the placebo group (n = 6). ENT-01 was well tolerated, with no deaths or drug-related serious adverse events. Adverse events were predominantly gastrointestinal, including nausea (34.4% [ENT-01] vs. 5.3% [placebo]; P < 0.001) and diarrhea (19.4% [ENT-01] vs. 5.3% [placebo]; P = 0.016). LIMITATION: Longer treatment periods need to be investigated in future studies. CONCLUSION: ENT-01 was safe and significantly improved constipation. PRIMARY FUNDING SOURCE: Enterin, Inc.

Deconstructing normal pressure hydrocephalus: Ventriculomegaly as early sign of neurodegeneration.

Idiopathic normal pressure hydrocephalus (NPH) remains both oversuspected on clinical grounds and underconfirmed when based on immediate and sustained response to cerebrospinal fluid diversion. Poor long-term postshunt benefits and findings of neurodegenerative pathology in most patients with adequate follow-up suggest that hydrocephalic disorders appearing in late adulthood may often result from initially unapparent parenchymal abnormalities. We critically review the NPH literature, highlighting the near universal lack of blinding and controls, absence of specific clinical, imaging, or pathological features, and ongoing dependence for diagnostic confirmation on variable cutoffs of gait response to bedside fluid-drainage testing. We also summarize our long-term institutional experience, in which postshunt benefits in patients with initial diagnosis of idiopathic NPH persist in only 32% of patients at 36 months, with known revised diagnosis in over 25% (Alzheimer's disease, dementia with Lewy bodies, and progressive supranuclear palsy). We postulate that previously reported NPH cases with "dual" pathology (ie, developing a "second" disorder) more likely represent ventriculomegalic presentations of selected neurodegenerative disorders in which benefits from shunting may be short-lived, with a consequently unfavorable risk-benefit ratio. Ann Neurol 2017;82:503-513.

Functional neurological disorders in Parkinson disease.

OBJECTIVE: To ascertain demographic and clinical features of Parkinson disease (PD) associated with functional neurological features. METHODS: A standardised form was used to extract data from electronic records of 53 PD patients with associated functional neurological disorders (PD-FND) across eight movement disorders centres in the USA, Canada and Europe. These subjects were matched for age, gender and disease duration to PD patients without functional features (PD-only). Logistic regression analysis was used to compare both groups after adjusting for clustering effect. RESULTS: Functional symptoms preceded or co-occurred with PD onset in 34% of cases, nearly always in the most affected body side. Compared with PD-only subjects, PD-FND were predominantly female (68%), had longer delay to PD diagnosis, greater prevalence of dyskinesia (42% vs 18%; P=0.023), worse depression and anxiety (P=0.033 and 0.025, respectively), higher levodopa-equivalent daily dose (972±701 vs 741±559 mg; P=0.029) and lower motor severity (P=0.019). These patients also exhibited greater healthcare resource utilisation, higher use of [(123)I]FP-CIT SPECT and were more likely to have had a pre-existing psychiatric disorder (P=0.008) and family history of PD (P=0.036). CONCLUSIONS: A subtype of PD with functional neurological features is familial in one-fourth of cases and associated with more psychiatric than motor disability and greater use of diagnostic and healthcare resources than those without functional features. Functional manifestations may be prodromal to PD in one-third of patients.

Thalamic deep brain stimulation for orthostatic tremor: A multicenter international registry.

BACKGROUND: We report the accumulated experience with ventral intermediate nucleus deep brain stimulation for medically refractory orthostatic tremor. METHODS: Data from 17 patients were reviewed, comparing presurgical, short-term (0-48 months), and long-term (≥48 months) follow-up. The primary end point was the composite activities of daily living/instrumental activities of daily living score. Secondary end points included latency of symptoms on standing and treatment-related complications. RESULTS: There was a 21.6% improvement (P = 0.004) in the composite activities of daily living/instrumental activities of daily living score, which gradually attenuated (12.5%) in the subgroup of patients with an additional long-term follow-up (8 of 17). The latency of symptoms on standing significantly improved, both in the short-term (P = 0.001) and in the long-term (P = 0.018). Three patients obtained no/minimal benefit from the procedure. CONCLUSIONS: Deep brain stimulation of the ventral intermediate nucleus was, in general, safe and well tolerated, yielding sustained benefit in selected patients with medically refractory orthostatic tremor. © 2017 International Parkinson and Movement Disorder Society.

Subtyping monogenic disorders: Huntington disease.

Huntington disease is a highly disabling neurodegenerative disease characterized by psychiatric, cognitive, and motor deficits. The causal genetic mutation in huntingtin (Htt, also known as IT15), located on chromosome 4p16.3, leads to an expansion of a triplet coding for polyglutamine. The expansion is invariably associated with the disease when >39 repeats. Htt encodes for the protein huntingtin (HTT), which carries out many essential biological functions in the cell, in particular in the nervous system. The precise mechanism of toxicity is not known. Based on a one-gene-one-disease framework, the prevailing hypothesis ascribes toxicity to the universal aggregation of HTT. However, the aggregation process into mutant huntingtin (mHTT) is associated with a reduction of the levels of wild-type HTT. A loss of wild-type HTT may plausibly be pathogenic, contributing to the disease onset and progressive neurodegeneration. Moreover, many other biological pathways are altered in Huntington disease, such as in the autophagic system, mitochondria, and essential proteins beyond HTT, potentially explaining biological and clinical differences among affected individuals. As one gene does not mean one disease, future efforts at identifying specific Huntington subtypes are important to design biologically tailored therapeutic approaches that correct the corresponding biological pathways-rather than continuing to exclusively target the common denominator of HTT aggregation for elimination.

Psychogenic facial movement disorders: clinical features and associated conditions.

The facial phenotype of psychogenic movement disorders has not been fully characterized. Seven tertiary-referral movement disorders centers using a standardized data collection on a computerized database performed a retrospective chart review of psychogenic movement disorders involving the face. Patients with organic forms of facial dystonia or any medical or neurological disorder known to affect facial muscles were excluded. Sixty-one patients fulfilled the inclusion criteria for psychogenic facial movement disorders (91.8% females; age: 37.0 ± 11.3 years). Phasic or tonic muscular spasms resembling dystonia were documented in all patients most commonly involving the lips (60.7%), followed by eyelids (50.8%), perinasal region (16.4%), and forehead (9.8%). The most common pattern consisted of tonic, sustained, lateral, and/or downward protrusion of one side of the lower lip with ipsilateral jaw deviation (84.3%). Ipsi- or contralateral blepharospasm and excessive platysma contraction occurred in isolation or combined with fixed lip dystonia (60.7%). Spasms were reported as painful in 24.6% of cases. Symptom onset was abrupt in most cases (80.3%), with at least 1 precipitating psychological stress or trauma identified in 57.4%. Associated body regions involved included upper limbs (29.5%), neck (16.4%), lower limbs (16.4%), and trunk (4.9%). There were fluctuations in severity and spontaneous exacerbations and remissions (60%). Prevalent comorbidities included depression (38.0%) and tension headache (26.4%). Fixed jaw and/or lip deviation is a characteristic pattern of psychogenic facial movement disorders, occurring in isolation or in combination with other psychogenic movement disorders or other psychogenic features.

Differential response of speed, amplitude, and rhythm to dopaminergic medications in Parkinson's disease.

Although movement impairment in Parkinson's disease includes slowness (bradykinesia), decreased amplitude (hypokinesia), and dysrhythmia, clinicians are instructed to rate them in a combined 0-4 severity scale using the Unified Parkinson's Disease Rating Scale motor subscale. The objective was to evaluate whether bradykinesia, hypokinesia, and dysrhythmia are associated with differential motor impairment and response to dopaminergic medications in patients with Parkinson's disease. Eighty five Parkinson's disease patients performed finger-tapping (item 23), hand-grasping (item 24), and pronation-supination (item 25) tasks OFF and ON medication while wearing motion sensors on the most affected hand. Speed, amplitude, and rhythm were rated using the Modified Bradykinesia Rating Scale. Quantitative variables representing speed (root mean square angular velocity), amplitude (excursion angle), and rhythm (coefficient of variation) were extracted from kinematic data. Fatigue was measured as decrements in speed and amplitude during the last 5 seconds compared with the first 5 seconds of movement. Amplitude impairments were worse and more prevalent than speed or rhythm impairments across all tasks (P < .001); however, in the ON state, speed scores improved exclusively by clinical (P < 10(-6) ) and predominantly by quantitative (P < .05) measures. Motor scores from OFF to ON improved in subjects who were strictly bradykinetic (P < .01) and both bradykinetic and hypokinetic (P < 10(-6) ), but not in those strictly hypokinetic. Fatigue in speed and amplitude was not improved by medication. Hypokinesia is more prevalent than bradykinesia, but dopaminergic medications predominantly improve the latter. Parkinson's disease patients may show different degrees of impairment in these movement components, which deserve separate measurement in research studies. © 2011 Movement Disorder Society.

The modified bradykinesia rating scale for Parkinson's disease: reliability and comparison with kinematic measures.

Bradykinesia encompasses slowness, decreased movement amplitude, and dysrhythmia. Unified Parkinson's Disease Rating Scale-based bradykinesia-related items require that clinicians condense abnormalities in speed, amplitude, fatiguing, hesitations, and arrests into a single score. The objective of this study was to evaluate the reliability of a modified bradykinesia rating scale, which separately assesses speed, amplitude, and rhythm and its correlation with kinematic measures from motion sensors. Fifty patients with Parkinson's disease performed Unified Parkinson's Disease Rating Scale-directed finger tapping, hand grasping, and pronation-supination while wearing motion sensors. Videos were rated blindly and independently by 4 clinicians. The modified bradykinesia rating scale and Unified Parkinson's Disease Rating Scale demonstrated similar inter- and intrarater reliability. Raters placed greater weight on amplitude than on speed or rhythm when assigning a Unified Parkinson's Disease Rating Scale score. Modified bradykinesia rating scale scores for speed, amplitude, and rhythm correlated highly with quantitative kinematic variables. The modified bradykinesia rating scale separately captures bradykinesia components with interrater and intrarater reliability similar to that of the Unified Parkinson's Disease Rating Scale. Kinematic sensors can accurately quantify speed, amplitude, and rhythm to aid in the development and evaluation of novel therapies in Parkinson's disease.

Current Directions in Deep Brain Stimulation for Parkinson's Disease-Directing Current to Maximize Clinical Benefit.

Several single-center studies and one large multicenter clinical trial demonstrated that directional deep brain stimulation (DBS) could optimize the volume of tissue activated (VTA) based on the individual placement of the lead in relation to the target. The ability to generate axially asymmetric fields of stimulation translates into a broader therapeutic window (TW) compared to conventional DBS. However, changing the shape and surface of stimulating electrodes (directional segmented vs. conventional ring-shaped) also demands a revision of the programming strategies employed for DBS programming. Model-based approaches have been used to predict the shape of the VTA, which can be visualized on standardized neuroimaging atlases or individual magnetic resonance imaging. While potentially useful for optimizing clinical care, these systems remain limited by factors such as patient-specific anatomical variability, postsurgical lead migrations, and inability to account for individual contact impedances and orientation of the systems of fibers surrounding the electrode. Alternative programming tools based on the functional assessment of stimulation-induced clinical benefits and side effects allow one to collect and analyze data from each electrode of the DBS system and provide an action plan of ranked alternatives for therapeutic settings based on the selection of optimal directional contacts. Overall, an increasing amount of data supports the use of directional DBS. It is conceivable that the use of directionality may reduce the need for complex programming paradigms such as bipolar configurations, frequency or pulse width modulation, or interleaving. At a minimum, stimulation through directional electrodes can be considered as another tool to improve the benefit/side effect ratio. At a maximum, directionality may become the preferred way to program because of its larger TW and lower energy consumption.

Thalamic Deep Brain Stimulation for tremor: The critical role of intraoperative testing.

INTRODUCTION: Optimal placement of Deep Brain Stimulation (DBS) lead is critical to ensure an adequate therapeutic benefit and minimize stimulation-induced side effects. METHODS: We reviewed data from 2004 to 2018 of all cases of essential tremor treated with thalamic DBS at the University of Cincinnati. All procedures were performed with the patient awake. Change in parallel trajectory was classified as major repositioning, whereas a change in depth of electrode classified as minor repositioning. The following data were compared between groups (no vs. minor vs. major repositioning): age at surgery, sex, AC-PC length, third ventricle width, cerebral atrophy, small vessel disease burden, and intraoperative tremor control. Univariate and multivariate analyses were conducted to identify factors associated with intraoperative repositioning. RESULTS: Of the 127 encounters with essential tremor, 71 required repositioning (33 major and 38 minor). Comparing procedures with major, minor, and no repositioning, mean number of changes per procedure (4 vs. 1.2 vs 0; p < 0.001) and AC-PC length (26 vs. 27 vs. 27.2 mm; p = 0.021) differed between the three groups. Older age at surgery (OR 1.04, p = 0.042), left side (OR 2.56, p = 0.04) and decrease in AC-PC length (OR 1.33, p = 0.026) were associated with greater odds of any (minor or major) repositioning. A decrease in AC-PC length was associated with greater odds of major repositioning (OR 1.37, p = 0.009). CONCLUSION: Intraoperative functional testing may be critical to ensure the accuracy of thalamic DBS targeting based on neuroimaging data, particularly in patients with reduced AC-PC length.

Phenotype-Agnostic Molecular Subtyping of Neurodegenerative Disorders: The Cincinnati Cohort Biomarker Program (CCBP).

Ongoing biomarker development programs have been designed to identify serologic or imaging signatures of clinico-pathologic entities, assuming distinct biological boundaries between them. Identified putative biomarkers have exhibited large variability and inconsistency between cohorts, and remain inadequate for selecting suitable recipients for potential disease-modifying interventions. We launched the Cincinnati Cohort Biomarker Program (CCBP) as a population-based, phenotype-agnostic longitudinal study. While patients affected by a wide range of neurodegenerative disorders will be deeply phenotyped using clinical, imaging, and mobile health technologies, analyses will not be anchored on phenotypic clusters but on bioassays of to-be-repurposed medications as well as on genomics, transcriptomics, proteomics, metabolomics, epigenomics, microbiomics, and pharmacogenomics analyses blinded to phenotypic data. Unique features of this cohort study include (1) a reverse biology-to-phenotype direction of biomarker development in which clinical, imaging, and mobile health technologies are subordinate to biological signals of interest; (2) hypothesis free, causally- and data driven-based analyses; (3) inclusive recruitment of patients with neurodegenerative disorders beyond clinical criteria-meeting patients with Parkinson's and Alzheimer's diseases, and (4) a large number of longitudinally followed participants. The parallel development of serum bioassays will be aimed at linking biologically suitable subjects to already available drugs with repurposing potential in future proof-of-concept adaptive clinical trials. Although many challenges are anticipated, including the unclear pathogenic relevance of identifiable biological signals and the possibility that some signals of importance may not yet be measurable with current technologies, this cohort study abandons the anchoring role of clinico-pathologic criteria in favor of biomarker-driven disease subtyping to facilitate future biosubtype-specific disease-modifying therapeutic efforts.

Safety and Tolerability of SRX246, a Vasopressin 1a Antagonist, in Irritable Huntington's Disease Patients-A Randomized Phase 2 Clinical Trial.

SRX246 is a vasopressin (AVP) 1a receptor antagonist that crosses the blood-brain barrier. It reduced impulsive aggression, fear, depression and anxiety in animal models, blocked the actions of intranasal AVP on aggression/fear circuits in an experimental medicine fMRI study and demonstrated excellent safety in Phase 1 multiple-ascending dose clinical trials. The present study was a 3-arm, multicenter, randomized, placebo-controlled, double-blind, 12-week, dose escalation study of SRX246 in early symptomatic Huntington's disease (HD) patients with irritability. Our goal was to determine whether SRX246 was safe and well tolerated in these HD patients given its potential use for the treatment of problematic neuropsychiatric symptoms. Participants were randomized to receive placebo or to escalate to 120 mg twice daily or 160 mg twice daily doses of SRX246. Assessments included standard safety tests, the Unified Huntington's Disease Rating Scale (UHDRS), and exploratory measures of problem behaviors. The groups had comparable demographics, features of HD and baseline irritability. Eighty-two out of 106 subjects randomized completed the trial on their assigned dose of drug. One-sided exact-method confidence interval tests were used to reject the null hypothesis of inferior tolerability or safety for each dose group vs. placebo. Apathy and suicidality were not affected by SRX246. Most adverse events in the active arms were considered unlikely to be related to SRX246. The compound was safe and well tolerated in HD patients and can be moved forward as a candidate to treat irritability and aggression.

Subthalamic nucleus deep brain stimulation with a multiple independent constant current-controlled device in Parkinson's disease (INTREPID): a multicentre, double-blind, randomised, sham-controlled study.

BACKGROUND: Deep brain stimulation (DBS) of the subthalamic nucleus is an established therapeutic option for managing motor symptoms of Parkinson's disease. We conducted a double-blind, sham-controlled, randomised controlled trial to assess subthalamic nucleus DBS, with a novel multiple independent contact current-controlled (MICC) device, in patients with Parkinson's disease. METHODS: This trial took place at 23 implanting centres in the USA. Key inclusion criteria were age between 22 and 75 years, a diagnosis of idiopathic Parkinson's disease with over 5 years of motor symptoms, and stable use of anti-parkinsonian medications for 28 days before consent. Patients who passed screening criteria were implanted with the DBS device bilaterally in the subthalamic nucleus. Patients were randomly assigned in a 3:1 ratio to receive either active therapeutic stimulation settings (active group) or subtherapeutic stimulation settings (control group) for the 3-month blinded period. Randomisation took place with a computer-generated data capture system using a pre-generated randomisation table, stratified by site with random permuted blocks. During the 3-month blinded period, both patients and the assessors were masked to the treatment group while the unmasked programmer was responsible for programming and optimisation of device settings. The primary outcome was the difference in mean change from baseline visit to 3 months post-randomisation between the active and control groups in the mean number of waking hours per day with good symptom control and no troublesome dyskinesias, with no increase in anti-parkinsonian medications. Upon completion of the blinded phase, all patients received active treatment in the open-label period for up to 5 years. Primary and secondary outcomes were analysed by intention to treat. All patients who provided informed consent were included in the safety analysis. The open-label phase is ongoing with no new enrolment, and current findings are based on the prespecified interim analysis of the first 160 randomly assigned patients. The study is registered with ClinicalTrials.gov, NCT01839396. FINDINGS: Between May 17, 2013, and Nov 30, 2017, 313 patients were enrolled across 23 sites. Of these 313 patients, 196 (63%) received the DBS implant and 191 (61%) were randomly assigned. Of the 160 patients included in the interim analysis, 121 (76%) were randomly assigned to the active group and 39 (24%) to the control group. The difference in mean change from the baseline visit (post-implant) to 3 months post-randomisation in increased ON time without troublesome dyskinesias between the active and control groups was 3·03 h (SD 4·52, 95% CI 1·3-4·7; p<0·0001). 26 serious adverse events in 20 (13%) patients occurred during the 3-month blinded period. Of these, 18 events were reported in the active group and 8 in the control group. One death was reported among the 196 patients before randomisation, which was unrelated to the procedure, device, or stimulation. INTERPRETATION: This double-blind, sham-controlled, randomised controlled trial provides class I evidence of the safety and clinical efficacy of subthalamic nucleus DBS with a novel MICC device for the treatment of motor symptoms of Parkinson's disease. Future trials are needed to investigate potential benefits of producing a more defined current field using MICC technology, and its effect on clinical outcomes. FUNDING: Boston Scientific.

Nutritional ketosis for mild cognitive impairment in Parkinson's disease: A controlled pilot trial.

INTRODUCTION: Glucose hypometabolism and insulin resistance increase risk for and accelerate progression in Parkinson's disease and neurocognitive disorders. We conducted a proof of concept trial to determine whether ketogenesis, a metabolic adaptation induced by dietary carbohydrate restriction, can improve cognitive performance in Parkinson's disease patients with mild cognitive impairment. METHODS: We enrolled patients with mild cognitive impairment associated with Parkinson's disease in an eight-week nutritional intervention with random assignment to either high-carbohydrate consumption typical of the Western dietary pattern (n = 7) or to a low-carbohydrate, ketogenic regimen (n = 7). We assessed changes in cognitive performance as well as motor function, anthropometrics, and metabolic parameters. RESULTS: Relative to the high-carbohydrate group, the low-carbohydrate group demonstrated improvements in lexical access (p = 0.02, Cohen's f effect size = 0.76) and memory (p = 0.01, f = 0.87) and as well as a trend for reduced interference in memory (p = 0.06, f = 0.60). The low-carbohydrate group also exhibited reduced body weight (p < 0.0001, f = 1.89) and increased circulation of beta-hydroxybutyrate (p = 0.01, f = 0.90). Change in body weight was strongly associated with memory performance (p = 0.001). Motor function was not affected by the intervention. CONCLUSION: Nutritional ketosis enhanced cognitive performance in Parkinson's disease-associated mild cognitive impairment in this pilot study. This metabolic intervention and its mechanisms deserve further investigation in the context of neurodegeneration.

Subthalamic deep brain stimulation and levodopa in Parkinson's disease: a meta-analysis of combined effects.

INTRODUCTION: While subthalamic nucleus deep brain stimulation (STN-DBS) and levodopa improve motor symptoms in Parkinson disease (PD) to a similar magnitude, their combined effect remains unclear. We sought to evaluate whether STN-DBS and levodopa yield differential effects on motor outcomes, dyskinesia, and activities of daily living (ADL) when combined compared to when administered alone. METHODS: We conducted a meta-analysis of all studies reporting motor, dyskinesia, and ADL outcomes after bilateral STN-DBS in PD with presurgical Unified Parkinson's Disease Rating Scale (UPDRS-III) in Medication-OFF and Medication-ON states and postsurgical assessments in four conditions: Stimulation-ON/Medication-ON, Stimulation-ON/Medication-OFF, Stimulation-OFF/Medication-ON, and Stimulation-OFF/Medication-OFF. Dyskinesia duration (UPDRS item 32) and ADL (UPDRS-II) were compared between high and low postsurgical levodopa equivalent daily dose (LEDD) reduction. Random-effects meta-analyses using generic-inverse variance were conducted. Confidence in outcomes effect sizes was assessed. RESULTS: Twelve studies were included (n = 401 patients). Stimulation-ON/Medication-ON was associated with an UPDRS-III improvement of - 35.7 points [95% confidence interval, - 40.4, - 31.0] compared with Stimulation-OFF/Medication-OFF, - 11.2 points [- 14.0, - 8.4] compared with Stimulation-OFF/Medication-ON, and - 9.5 points [- 11.0, - 8.0] compared to Stimulation-ON/Medication-OFF within 5 years. The difference was maintained beyond 5 years by - 28.6 [- 32.8, - 24.4], - 8.1 [- 10.2, - 5.9], and - 8.0 [- 10.3, - 5.6], respectively. No difference was observed between Stimulation-ON/Medication-OFF and Stimulation-OFF/Medication-ON within and beyond 5 years. Dyskinesia duration and ADL outcomes were similar in high vs. low postsurgical LEDD reduction. CONCLUSION: Subthalamic nucleus deep brain stimulation and levodopa independently lessened motor severity in PD to a similar magnitude, but their combined effect was greater than either treatment alone, suggesting therapeutic synergism.

Association of Subthalamic Deep Brain Stimulation With Motor, Functional, and Pharmacologic Outcomes in Patients With Monogenic Parkinson Disease: A Systematic Review and Meta-analysis.

Importance: Comparative outcomes among different monogenic forms of Parkinson disease after subthalamic nucleus deep brain stimulation (STN DBS) remain unclear. Objective: To compare clinical outcomes in patients with the most common monogenic forms of Parkinson disease treated with STN DBS. Design, Setting, and Participants: Systematic review and meta-analysis in which a PubMed search of interventional and noninterventional studies of Parkinson disease with LRRK2, GBA, or PRKN gene mutations published between January 1, 1990, and May 1, 2018, was conducted. Among the inclusion criteria were articles that reported the Motor subscale of the Unified Parkinson's Disease Rating Scale Part III (UPDRS-III) before and after STN DBS treatment, that involved human participants, and that were published in the English language. Studies that used aggregated data from patients with different genetic mutations were excluded, and so were studies with assumed but not confirmed genetic data or incomplete follow-up data. Main Outcomes and Measures: Changes in UPDRS-III scores and levodopa equivalent daily dose (LEDD) were analyzed for each monogenic form of Parkinson disease. Additional end points included activities of daily living (UPDRS-II), motor complications (UPDRS-IV), and cognitive function. Results: Of the 611 eligible studies, 17 (2.8%) met the full inclusion criteria; these 17 studies consisted of 8 cohort studies (47.1%), 3 case series (17.6%), and 6 case reports (35.3%), and they involved a total of 518 patients. The UPDRS-III score improved by 46% in LRRK2 (mean change, 23.0 points; 95% CI, 15.2-30.8; P < .001), 49% in GBA (20.0 points; 95% CI, 4.5-35.5; P = .01), 43% in PRKN (24.1 points; 95% CI, 12.4-35.9; P < .001), and 53% in idiopathic Parkinson disease (25.2 points; 95% CI, 21.3-29.2; P < .001). The LEDD was reduced by 61% in LRRK2 (mean change, 711.9 mg/d; 95% CI, 491.8-932.0; P < .001), 22% in GBA (269.2 mg/d; 95% CI, 226.8-311.5; P < .001), 61% in PRKN (494.8 mg/d; 95% CI, -18.1 to -1007.8; P = .06), and 55% in idiopathic Parkinson disease (681.8 mg/d; 95% CI, 544.4-819.1; P < .001). Carriers of the PRKN mutations showed sustained improvements in UPDRS-II and UPDRS-IV, whereas LRRK2 mutation carriers sustained improvements only in UPDRS-IV. Carriers of the GBA mutation showed worse postsurgical cognitive and functional performance. Conclusions and Relevance: Treatment with STN DBS for patients with Parkinson disease with LRRK2, GBA, or PRKN mutations appears to be associated with similar motor outcomes but different changes in dopaminergic dose, activities of daily living, motor complications, and cognitive functions.