Serotonin transporter density in isolated rapid eye movement sleep behavioral disorder.

Background/objective: The serotoninergic nervous system is known to play a role in the maintenance of rapid eye movement (REM) sleep. Serotoninergic projections are known to be vulnerable in synucleinopathies. To date, positron emission tomography (PET) studies using serotonin-specific tracers have not been reported in isolated REM sleep behavior disorder (iRBD). Methods: We conducted a cross-sectional imaging study using serotonin transporter (SERT) 11C-3-amino-4-(2-dimethylaminomethyl-phenylsulfaryl)-benzonitrile (DASB) PET to identify differences in serotonin system integrity between 11 participants with iRBD and 16 older healthy controls. Results: Participants with iRBD showed lower DASB distribution volume ratios (DVRs) in the total neocortical mantle [1.13 (SD: 0.07) vs. 1.19 (SD: 0.06); t = 2.33, p = 0.028)], putamen [2.07 (SD: 0.19) vs. 2.25 (SD: 0.18); t = 2.55, p = 0.017], and insula [1.26 (SD: 0.11) vs. 1.39 (SD: 0.09); t = 3.58, p = 0.001]. Paradoxical increases relative to controls were seen in cerebellar hemispheres [0.98 (SD: 0.04) vs. 0.95 (SD: 0.02); t = 2.93, p = 0.007)]. No intergroup differences were seen in caudate, substantia nigra, or other brainstem regions with the exception of the dorsal mesencephalic raphe [3.08 (SD: 0.53) vs. 3.47 (SD: 0.48); t = 2.00, p = 0.056] that showed a non-significant trend toward lower values in iRBD. Conclusions: Insular, neocortical, and striatal serotoninergic terminal loss may be common in prodromal synucleinopathies before the onset of parkinsonism or dementia. Given our small sample size, these results should be interpreted as hypothesis-generating/exploratory in nature.

Epidemiology of asylum seekers and refugees at the Mexico-US border: a cross-sectional analysis from the migrant settlement camp in Matamoros, Mexico.

BACKGROUND: The number of migrants and asylum seekers at the Mexico-US border has increased to historic levels. Our objective was to determine the medical diagnoses and treatments of migrating people seeking care in humanitarian clinics in Matamoros, Mexico. METHODS: We conducted a cross-sectional study of patient encounters by migrating people through a humanitarian clinic in Matamoros, Mexico, from November 22, 2019, to March 18, 2021. The clinics were operated by Global Response Medicine in concert with local non-governmental organizations. Clinical encounters were each coded to the appropriate ICD-10/CPT code and categorized according to organ system. We categorized medications using the WHO List of Essential Medicines and used multivariable logistic regression to determine associations between demographic variables and condition frequency. RESULTS: We found a total of 8,156 clinical encounters, which included 9,744 diagnoses encompassing 132 conditions (median age 26.8 years, female sex 58.2%). People originated from 24 countries, with the majority from Central America (n = 5598, 68.6%). The most common conditions were respiratory (n = 1466, 15.0%), musculoskeletal (n = 1081, 11.1%), and skin diseases (n = 473, 4.8%). Children were at higher risk for respiratory disease (aOR = 1.84, 95% CI: 1.61-2.10), while older adults had greater risk for joint disorders (aOR = 3.35, 95% CI: 1.73-6.02). Women had decreased risk for injury (aOR = 0.50, 95% CI: 0.40-0.63) and higher risk for genitourinary diseases (aOR = 4.99, 95% CI: 3.72-6.85) compared with men. Among 10,405 medications administered, analgesics were the most common (n = 3190, 30.7%) followed by anti-infectives (n = 2175, 21.1%). CONCLUSIONS: In this large study of a migrating population at the Mexico-US border, we found a variety of clinical conditions, with respiratory, musculoskeletal, and skin illnesses the most common in this study period which encompassed a period of restrictive immigration policy and the first year of the COVID-19 pandemic.

Regional serotonin terminal density in aging human brain: A [11C]DASB PET study.

There are conflicting results regarding regional age-related changes in serotonin terminal density in human brain. Some imaging studies suggest age-related declines in serotoninergic terminals and perikarya. Other human imaging studies and post-mortem biochemical studies suggest stable brain regional serotoninergic terminal densities across the adult lifespan. In this cross-sectional study, we used [11C]3-amino-4-(2-dimethylaminomethylphenylsulfanyl)-benzonitrile positron emission tomography to quantify brain regional serotonin transporter density in 46 normal subjects, ranging from 25 to 84 years of age. Both voxel-based analyses, using sex as a covariate, and volume-of-interest-based analyses were performed. Both analyses revealed age-related declines in [11C]3-amino-4-(2-dimethylaminomethylphenylsulfanyl)-benzonitrile binding in numerous brain regions, including several neocortical regions, striatum, amygdala, thalamus, dorsal raphe, and other subcortical regions. Similar to some other neurotransmitter systems of subcortical origin, we found evidence of age-related declines in regional serotonin terminal density in both cortical and subcortical regions.

Lecanemab: Looking Before We Leap.

Lecanemab, a novel amyloid-sequestering agent, recently received accelerated Food and Drug Administration approval for the treatment of mild dementia due to Alzheimer disease (AD) and mild cognitive impairment (MCI). Approval was based on a large phase 3 trial, Clarity, which demonstrated reductions in amyloid plaque burden and cognitive decline with lecanemab. Three major concerns should give us pause before adopting this medication: Its beneficial effects are small, its harms are substantial, and its potential costs are unprecedented. Although lecanemab has a clear and statistically significant effect on cognition, its effect size is small and may not be clinically significant. The magnitude of lecanemab's cognitive effect is smaller than independent estimates of the minimally important clinical difference, implying that the effect may be imperceptible to a majority of patients and caregivers. Lecanemab's cognitive effects were numerically smaller than the effect of cholinesterase inhibitors and may be much smaller. The main argument in lecanemab's favor is that it may lead to greater cognitive benefit over time. Although plausible, there is a lack of evidence to support this conclusion. Lecanemab's harms are substantial. In Clarity, it caused symptomatic brain edema in 11% and symptomatic intracranial bleeding in 0.5% of participants. These estimates likely significantly underestimate these risks in general practice for 3 reasons: (1) Lecanemab likely interacts with other medications that increase bleeding, an effect minimized in Clarity. (2) The Clarity population is much younger than the real-world population with mild AD dementia and MCI (age 71 years vs 85 years) and bleeding risk increases with age. (3) Bleeding rates in trials are typically much lower than in clinical practice. Lecanemab's costs are unprecedented. Its proposed price of $26,500 is based on cost-effectiveness analyses with tenuous assumptions. However, even if cost-effective, it is likely to result in higher expenditures than any other medication. If its entire target population were treated, the aggregate medication expenditures would be $120 billion US dollars per year-more than is currently spent on all medications in Medicare Part D. Before adopting lecanemab, we need to know that lecanemab is not less effective, vastly more harmful, and 100× more costly than donepezil.

Neighborhood Social Determinants of Health in Patients Seen in Neurology Movement Disorders Clinics.

Background and Objectives: Chronic health conditions are influenced by social determinants of health (SDH) including neighborhood-linked markers of affluence. We explored whether neighborhood socioeconomic factors differ in people with different types of clinical movement disorders (MDs). Methods: We conducted a retrospective study of patients seen in MD clinics at our center in 2021. Patient data were linked to the US National Neighborhood Data Archive linked to US census tract data. We evaluated variations in neighborhood socioeconomic factors across 8 different categories of MDs. Results: Compared with the neighborhoods of patients with Parkinson disease, neighborhoods of patients with cerebellar ataxias, functional movement disorders, and Huntington disease were characterized by higher proportions of people earning less than 15,000 US dollars/year, people receiving public assistance, and people with less than a high school diploma. Discussion: Neighborhood-linked SDH vary among different MDs. These findings have implications for public health interventions aimed at improving the care of people affected by MDs.

Ethical Aspects of Prodromal Synucleinopathy Prognostic Counseling.

Alpha-synucleinopathies can be identified in their prodromal phase, raising several ethical issues. In this review, we first provide definitions of prodromal α-synucleinopathies and discuss the importance of distinguishing between prodromes and risk factors. Next, we discuss the implications of a diagnosis of prodromal α-synucleinopathy and considerations regarding prognostic counseling in both clinical and research settings. We review available data on patient preferences regarding disclosure as well as providers' perspectives. We examine the pros and cons of disclosing a diagnosis of prodromal α-synucleinopathy, taking into consideration the differences between clinical and research settings. Asking about willingness to know in clinical and research settings and the shared decision-making process applied to prognostic counseling is discussed. Concerning research settings, ethical aspects regarding clinical trials are addressed. Availability of direct-to-consumer technologies will likely lead to novel contexts requiring prognostic counseling, and future neuroprotective or neuromodulating treatments may require further considerations on the timing, role, and importance of prognostic counseling. Recommendations on how to address ethical gaps should be a priority for patients, medical professional societies, and research workgroups. Ethical issues must be considered as an integral part of the overall clinical and research approach to prodromal synucleinopathies.

Serotonin Transporter Imaging in Multiple System Atrophy and Parkinson's Disease.

BACKGROUND: Both Parkinson's disease (PD) and multiple system atrophy (MSA) exhibit degeneration of brainstem serotoninergic nuclei, affecting multiple subcortical and cortical serotoninergic projections. In MSA, medullary serotoninergic neuron pathology is well documented, but serotonin system changes throughout the rest of the brain are less well characterized. OBJECTIVES: To use serotonin transporter [11 C]3-amino-4-(2-dimethylaminomethyl-phenylsulfaryl)-benzonitrile positron emission tomography (PET) to compare serotoninergic innervation in patients with MSA and PD. METHODS: We performed serotonin transporter PET imaging in 18 patients with MSA, 23 patients with PD, and 16 healthy controls to explore differences in brainstem, subcortical, and cortical regions of interest. RESULTS: Patients with MSA showed lower serotonin transporter distribution volume ratios compared with patients with PD in the medulla, raphe pontis, ventral striatum, limbic cortex, and thalamic regions, but no differences in the dorsal striatal, ventral anterior cingulate, or total cortical regions. Controls showed greater cortical serotonin transporter binding compared with PD or MSA groups but lower serotonin transporter binding in the striatum and other relevant basal ganglia regions. There were no regional differences in binding between patients with MSA-parkinsonian subtype (n = 8) and patients with MSA-cerebellar subtype (n = 10). Serotonin transporter distribution volume ratios in multiple different regions of interest showed an inverse correlation with the severity of Movement Disorders Society Unified Parkinson's Disease Rating Scale motor score in patients with MSA but not patients with PD. CONCLUSIONS: Brainstem and some forebrain subcortical region serotoninergic deficits are more severe in MSA compared with PD and show an MSA-specific correlation with the severity of motor impairments. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Cognitive correlates of dual tasking costs on the timed up and go test in Parkinson disease.

Introduction: Dual tasking impairments are an increasingly recognized contributor to falls in Parkinson disease (PD) and may be a promising therapeutic target for PD fall prevention trials. Depending on the context, ambulatory dual tasking difficulties may be caused by different types of neurocognitive impairments. Methods: We performed a cross-sectional analysis of 21 participants with PD. All participants underwent detailed neuropsychological testing that was quantified using normative z-scores. All participants completed the 3-meter timed up and go test (TUG), with and without a dual tasking assignment. Biomechanistic properties of the TUG were quantified using APDM wearable OPAL sensors. We explored correlations between dual tasking cost (DTC) in 1) total TUG duration, 2) Sit-to-stand duration, 3) Stand-to-sit duration, and 4) turn velocity. Results: Impaired total DTC in the TUG correlated inversely with global cognitive performance measured using the Montreal Cognitive Assessment (MoCA) (r = -0.4649, p = 0.0337). Sit-to-stand DTC impairments correlated inversely with processing speed on the WAIS-IV Coding (r = -0.5762, p = 0.0063), semantic fluency (r = -0.5100, p = 0.0182) and learning and memory on the Hopkins Verbal Learning Test-Revised total recall (r = -0.5502, p = 0.0098). Impaired stand-to-sit DTC function corelated inversely with visuospatial cognitive function on the Benton Judgement of Line Orientation (JOLO) test (r = -0.5181, p = 0.0161). Conclusions: The link between dual tasking and fall risk in PD may be caused by cognitive features other than executive dysfunction and may vary based on the ambulatory task in question. These findings shed light on the cognitive contributions to falls in PD.

Isolated REM sleep behavior disorder in North American older adults in an integrated health care system.

STUDY OBJECTIVE: Identifying individuals with isolated rapid eye movement sleep behavioral disorder (iRBD) is an important clinical research priority for future synucleinopathy trials. Nevertheless, little is known about the breadth of clinical settings where diagnoses of iRBD are initially made. METHODS: We conducted a retrospective cohort study using the electronic medical record system at the University of Michigan to identify patients aged ≥ 60 years with new diagnoses of iRBD between 2015 and 2020. We focused specifically on patients receiving primary care at the University of Michigan so that we might use the university's electronic medical record system to capture the full scope of their multispecialty care interactions and diagnoses in this integrated health care system. We used International Classification of Diseases, Ninth Revision and Tenth Revision, diagnosis codes to identify the time of initial clinical diagnosis. RESULTS: We found that 62/105 (59.0%) diagnoses were made by a sleep specialist, 9 (8.6%) by neurologists, and 30 (29.5%) by generalists or primary care (29.5%) providers. In addition, 67/105 (63.8%) diagnoses were made in the context of having available polysomnography results, while the remainder was made on the basis of clinical symptoms alone. The prognostic implications of iRBD were documented in 40/105 (38.1%) encounter notes and were more likely to occur in sleep clinic settings (chi-square = 12.74; P < .001) than in other contexts. CONCLUSIONS: Initial iRBD diagnoses occur in varied clinical settings in an integrated health care system and are often made without a confirmatory polysomnogram. Documented prognostic counseling is seen most often in sleep medicine clinics. Synucleinopathy prevention trials may be best designed around a sleep clinic-focused recruitment approach. CITATION: Havis I, Coates T, Wyant KJ, Spears CC, Garwood M, Kotagal V. Isolated REM sleep behavior disorder in North American older adults in an integrated health care system. J Clin Sleep Med. 2022;18(9):2173-2178.

Racial Differences in Trust and Risk Disclosure Preferences Among Older Registered Research Volunteers Screened for Prodromal Synucleinopathies.

Background/Objectives: The equitable enrollment of minority participants in synucleinopathy trials is an emerging public health concern. Differing views regarding risk disclosure may influence research involvement in at-risk adults. Methods: We conducted a brief mailed survey, including questions about trust and hypothetical risk disclosure preferences, to 100 participants in the Healthier Black Elders Center cohort in Detroit, MI and 100 participants in the Claude D. Pepper Older Americans Independence Center Research Participant Program at the University of Michigan. Results: 125 recipients without a diagnosis of a neurodegenerative disorder returned the survey, 52 (41.6%) of whom identified as being Black or African American. Black respondents reported less trust in medical providers (t=2.02, p=0.045) and medical researchers (t=2.52, p=0.013) and a greater desire to be informed about the presence of unchangeable risk factors for neurodegenerative disorders (t=2.02, p=0.045). Conclusions: These findings have implications for the recruitment of representative populations in prodromal neurodegenerative research.

Age and Life-Sustaining Treatment Preferences in Parkinson Disease.

OBJECTIVE: Advance Care Planning (ACP) is one of 10 key elements in the American Academy of Neurology Parkinson disease (PD) clinical practice quality measures. We know little about how aging influences ACP views in people with PD. METHODS: We conducted a cross-sectional survey of 39 participants (mean age 70.3 years; range: 52-81) with PD to explore correlations between older age and life-sustaining treatment preferences while controlling for confounders including years of education, Montreal Cognitive Assessment score and Movement Disorders Society Unified Parkinson's disease Rating Scale motor score. Scenarios asked participants to choose their level of interest in pursuing life-sustaining measures in the setting of specific medical illnesses including stroke, metastatic cancer, severe heart attack, and dementia. All participants were men and were recruited from the Veterans Affairs Ann Arbor Healthcare System. RESULTS: In the hypothetical stroke, metastatic colon cancer, and dementia scenarios, older age correlated with more aggressive care goals related to the use cardiopulmonary resuscitation to treat cardiopulmonary arrest. CONCLUSIONS: Advancing age in PD may correlate with paradoxically more aggressive goals as it relates to life-sustaining treatment preferences including cardiopulmonary resuscitation. This may reflect a response to heightened concern among older adults with PD about the potential for compromised autonomy in the setting of aging.

Psychedelic-assisted therapy for functional neurological disorders: A theoretical framework and review of prior reports.

Functional neurological disorders (FNDs), which are sometimes also referred to as psychogenic neurological disorders or conversion disorder, are common disabling neuropsychiatric disorders with limited treatment options. FNDs can present with sensory and/or motor symptoms, and, though they may mimic other neurological conditions, they are thought to occur via mechanisms other than those related to identifiable structural neuropathology and, in many cases, appear to be triggered and sustained by recognizable psychological factors. There is intriguing preliminary evidence to support the use of psychedelic-assisted therapy in a growing number of psychiatric illnesses, including FNDs. We review the theoretical arguments for and against exploring psychedelic-assisted therapy as a treatment for FNDs. We also provide an in-depth discussion of prior published cases detailing the use of psychedelics for psychosomatic conditions, analyzing therapeutic outcomes from a contemporary neuroscientific vantage as informed by several recent neuroimaging studies on psychedelics and FNDs.

Caregiver burden worsens in the second year after subthalamic nucleus deep brain stimulation for Parkinson's disease.

BACKGROUND: Caregiver burden (CB) in Parkinson's disease (PD) does not improve in the short term after bilateral subthalamic nucleus (STN) deep brain stimulation (DBS), despite motor improvement. This may be due to increased caregiver demands after surgery or the possibility that DBS unresponsive non-motor factors, such as executive dysfunction, contribute to CB. OBJECTIVE: To evaluate the trajectory of CB in year 2 following bilateral STN DBS surgery for PD, and to test whether post-operative CB changes correlate with changes in executive function in a subgroup with available neuropsychological testing. METHODS: This retrospective analysis included 35 patients with PD whose caregivers completed the Caregiver Burden Inventory (CBI) at baseline and between 9 and 24 months after bilateral STN DBS. 14 of these patients had neuropsychological testing both at baseline and within 6 months of their follow up CBI assessment. RESULTS: CBI scores showed worsened CB from baseline to follow-up (16.4-21.5, p = 0.006). There was no correlation between change in executive function and change in CBI in the smaller subsample. CONCLUSION: CB worsens in the 2 years after bilateral STN DBS despite improvement in motor symptoms and is not associated with change in executive dysfunction in the setting of advancing PD. These findings have implications on pre-operative counselling for patients and caregivers considering DBS for PD.

Thirty-Day Hospital Readmission and Surgical Complication Rates for Shunting in Normal Pressure Hydrocephalus: A Large National Database Analysis.

BACKGROUND: Research on age-related complications secondary to shunts in normal pressure hydrocephalus (NPH) is primarily limited to single-center studies and small cohorts. OBJECTIVE: To determine the rates of hospital readmission and surgical complications, and factors that predict them, following shunt surgery for NPH in a large healthcare network. METHODS: Surgical procedures, complications, and readmissions for adults undergoing ventricular shunting for NPH were determined using de-identified claims from a privately insured United States healthcare network in years 2007-2014. Univariate and multivariate statistics were used to determine factors that predict poor surgical outcomes. The primary outcome variable was surgical complications or readmissions (composite variable for any major perioperative complication or 30-d readmission). RESULTS: The 30-d readmission rate for 974 patients with NPH who underwent ventricular shunting was 7.29%; the most common reasons for readmission were shunt-related complications, infection, hemorrhage, altered mental status, and cardiopulmonary and musculoskeletal problems. The perioperative complication rate was 21.15%, including intraparenchymal hemorrhage (5.85%) and extra-axial (subdural or epidural) hematoma (5.54%). The overall rate of having a surgical complication or 30-d readmission was 25.15%. Age did not predict surgical complication or 30-d readmission. Preoperative comorbidities independently associated with poor outcome were myocardial infarction within 1 yr (OR = 3.984, 95% CI = 1.105-14.368); existing cerebrovascular disease (odds ratio [OR] = 2.206, 95% CI = 1.544-3.152); and moderate/severe renal disease (OR = 2.000, 95% CI = 1.155-3.464). CONCLUSION: The rate of complications or readmission within 30 d of ventricular shunting for NPH is 25.15%. Preoperative comorbidities of myocardial infarction within 1 yr, cerebrovascular disease, and moderate/severe renal disease are independent risk factors for poor outcome.

Apathy rating scores and ß-amyloidopathy in patients with Parkinson disease at risk for cognitive decline.

OBJECTIVE: To determine whether ß-amyloidopathy correlates with apathy rating scores independently of mood changes and other neurodegenerative processes in Parkinson disease (PD). METHODS: In this cross-sectional study, patients with PD (n = 64, 48 male and 16 female, mean age 69.2 ± 6.7 years, Hoehn & Yahr stage 2.7 ± 0.5, Montreal Cognitive Assessment score 25.3 ± 3.0) underwent [11C]Pittsburgh compound B ß-amyloid, [11C]dihydrotetrabenazine vesicular monoamine transporter type 2 (VMAT2), and [11C]methyl 4 piperidinyl propionate acetylcholinesterase brain PET imaging and clinical assessments, including the Marin Apathy Evaluation Scale, Clinician Version. Patients were recruited on the basis of having at least 1 risk factor for PD dementia, but they were excluded if they had dementia. RESULTS: Mean apathy rating score was 25.4 ± 6.4, reflecting predominantly subclinical apathy. Apathy rating scale scores correlated with amyloid binding, cognitive, depressive, and anxiety scores but not significantly with age, duration of disease, striatal VMAT2, or cholinergic binding. Multiple regression analysis model (p < 0.0001) showed significant regressor effects for global ß-amyloid burden (p = 0.0038) with significant covariate effects for global cognitive z scores (p = 0.028) and for anxiety (p = 0.038) but not with depressive scores. Voxel-based analysis showed robust correlation between apathy rating scale scores and ß-amyloid binding in bilateral nuclei accumbens, inferior frontal, and cingulate cortices (family-wise error rate-corrected p < 0.005). CONCLUSION: Apathy is independently associated with ß-amyloidopathy in patients with PD at risk of dementia. Regional brain findings are most robust for ß-amyloidopathy in the nuclei accumbens, inferior frontal, and cingulate regions. Findings may provide an explanation for the often treatment-refractory nature of apathy in advancing PD despite optimized dopaminergic and antidepressant pharmacotherapy. CLINICALTRIALSGOV IDENTIFIER: NCT01565473.

Fatigue in Parkinson's Disease Associates with Lower Ambulatory Diastolic Blood Pressure.

BACKGROUND/OBJECTIVE: Fatigue is a common debilitating symptom in Parkinson's disease (PD) of unclear etiology. Hypotension and blood pressure variability are common in PD though their relationship to other non-motor symptoms is less well understood. METHODS: We conducted a cross-sectional study to explore differences in 24-hour ambulatory blood pressure measurements in PD subjects (n = 35) with and without fatigue. Subjects underwent hourly systolic (SBP) and diastolic (DBP) blood pressure testing in their home environment. The presence of fatigue was assessed using the Movement Disorders Society Unified Parkinson's Disease Rating Scale (MDS-UPDRS) part 1. We compared blood pressure measurements in fatigued vs. non-fatigued PD subjects, assessed over 4 epochs: overnight, morning, midday, and evening. RESULTS: PD subjects with symptoms of fatigue demonstrated lower mean DBP, compared to those without fatigue (67.8±4.8 mmHg vs. 75.6±9.4 t = 2.57, p = 0.014). These intergroup differences were most notable in the morning. The two groups did not differ in scoring on the Survey of Autonomic Symptoms or on an office-based blood assessment of SBP or DBP performed on the day of 24-hour monitor initiation. CONCLUSIONS: Fatigue in PD may be a clinical manifestation of low-grade systemic hypotension.

The 10-year Landscape of United States-Registered Parkinson Disease Clinical Trials: 2007-2016.

BACKGROUND: We know little about how well the goals and results of clinical trials in Parkinson disease (PD) reflect the priorities of patients and the broader PD community. OBJECTIVES: We conducted a review of registered trials on http://clincialtrials.gov from 2007 to 2016 to explore whether PD trials have moved closer to the therapeutic priority goals articulated by the PD community. METHODS: Using the search terms: Parkinson, interventional trials, phase "0-4," we categorized therapeutic PD studies from http://clinicaltrials.gov between January 1, 2007 and December 31, 2016. Seven hundred and sixty-six trials met the criteria for analysis. We explored temporal trends in the utilization of balance problems and falls; mood symptoms, including stress and anxiety; cognitive dysfunction, including dementia; and dyskinesias as primary outcomes. We analyzed trials where recruitment was listed as "completed" (n = 391) to explore publication rates. RESULTS: Balance problems and falls were listed as primary outcome measures in 125 studies (16.3%), cognitive measures in 48 (6.3%), mood features in 37 (4.8%), and dyskinesias in 30 (3.9%). Trials using balance problems and falls as a primary outcome increased in frequency per year between 2007 and 2016 (Z = -2.128, p = 0.033) unlike the proportion of trials evaluating cognitive dysfunction including dementia (Z = -0.380, p = 0.704), mood symptoms including stress and anxiety (Z = 0.345, p = 0.730), or dyskinesias (Z = 0.340, p = 0.734), which did not show temporal changes. 231 (59.1%) completed trials had results published in manuscript form as of 5/1/2017, leaving 40.9% of trials unpublished. CONCLUSIONS: PD trials focusing on balance problems and falls are becoming more common. About 40% of completed PD trials are unpublished, reflecting suboptimal utilization of participant efforts.

Serious adverse events following Normal Pressure Hydrocephalus surgery.

OBJECTIVE: Recent Normal Pressure Hydrocephalus (NPH) practice guidelines describe a serious adverse event (SAE) rate following surgery of 11%. PATIENTS & METHODS: We conducted a retrospective review of 162 consecutive patients who have undergone work-up at our center's multidisciplinary NPH clinic over a 47 month time period (2/2014-12/2017). Of these, 22 ultimately underwent neurosurgical ventricular shunt surgery as treatment for NPH. Clinical records were reviewed for SAEs categorized as possibly/probably/definitely related to NPH surgery. RESULTS: In 10/22 (45.5%) operated subjects, there were 11 qualifying SAEs over this 3-year period: 1 central nervous system infections, 4 subdural hematomas, 2 seizures resulting in hospitalization, 1 catheter malfunction, 2 perioperative AEs, and 1 death of uncertain cause. Eight SAEs were coded as probably/definitely related. Six occurred >3 months from the time of surgery. CONCLUSIONS: SAEs following NPH surgery are common. Additional studies are needed to determine the long-term safety of NPH surgery in older adults.

Serotonin, ß-amyloid, and cognition in Parkinson disease.

OBJECTIVE: Serotoninergic neurotransmission may modulate ß-amyloid peptide (Aß) metabolism through upregulation of α-secretase. Early Parkinson disease (PD) shows variable serotoninergic denervation, which may impact Aß deposition. METHODS: We conducted 3 analyses to explore associations between serotoninergic neurotransmission and cerebral Aß burden in PD. The first was a cross-sectional imaging study of PD subjects (n = 23) using the serotoninergic transporter positron emission tomography (PET) ligand [11 C]3-amino-4-(2-dimethylaminomethyl-phenylsulfaryl)-benzonitrile (DASB) and amyloid PET Pittsburgh compound B ([11 C]PiB). The second was a baseline study of Parkinson's Progression Markers Initiative (PPMI) subjects exploring the influence of serotoninergic medications on cerebrospinal fluid (CSF) Aß-42 levels (n = 389), controlling for age, sex, Geriatric Depression Scale, disease duration, and education. Third, we fit an interval censored proportional hazard model with longitudinal PPMI data (n = 367) to test whether serotoninergic medication use associates with reduced risk of PD cognitive decline, defined as time to reach a Montreal Cognitive Assessment score ≤ 20, adjusting for baseline caudate dopamine transporter [123 I]ioflupane single photon emission computed tomography and CSF Aß-42 levels. RESULTS: Serotoninergic DASB distribution volume ratio (DVR) inversely associated with PiB DVR in the cerebral cortex (Pearson r = -0.478, p = 0.021) but not the striatum (r = -0.264, p = 0.224). In the baseline PPMI analysis, serotoninergic medication use for ≥6 months associated with a lower level of CSF Aß-42 (t = -2.20, p = 0.029). In the longitudinal PPMI model, baseline serotoninergic medication use associated with a reduced risk of cognitive decline (t = -2.03, p = 0.043) after controlling for covariates. INTERPRETATION: Cortical Aß burden in PD associates inversely with serotoninergic innervation. Serotoninergic medications may alter Aß metabolism and reduce the risk of PD cognitive decline. Ann Neurol 2018;83:994-1002.

Cardiovascular Risk Factor Burden in Veterans and Non-Veterans with Parkinson Disease.

BACKGROUND: Medical comorbidities, including cardiovascular risk factors such as hypertension and diabetes, influence disease progression in Parkinson disease (PD) and may be variably present in different clinical populations. OBJECTIVE/METHODS: We conducted a retrospective nested case-control study of 29 Veterans with PD and 29 non-Veteran PD controls. The groups were matched for age, gender, and disease duration. Both groups underwent clinical and imaging testing as part of their participation in a larger cross-sectional PD observational study at our research center. Veterans were recruited primarily from movement disorders neurology clinics at the Ann Arbor Veterans Affairs (VA) Health System. Non-Veterans were recruited primarily from analogous clinics at the University of Michigan Health System. We explored differences in cardiovascular risks factor burden between the groups. RESULTS: Veterans with PD showed higher scores on the simplified Framingham 10-year general cardiovascular disease risk calculator (FR score; 27.3% (11.5) vs. 20.7% (6.8); t = -2.66, p = 0.011) and fewer years of self-reported education (14.5 (2.5) vs. 16.7 (2.6); t = 3.33, p = 0.002). After adjusting for age, disease duration, education, and the use of antihypertensive medications, Veterans showed higher FR scores (t = 2.95, p = 0.005) and a higher intra-subject ratio of FR score to age-and-gender normalized FR score (t = 2.49, p = 0.016), representing an elevated component of modifiable cardiovascular risk factor burden. CONCLUSION: Cardiovascular comorbidities are common in Veterans with PD and may be more severe than in non-Veteran PD populations. These findings merit replication in other representative cohorts. Veterans may be a preferred population for clinical trials evaluating cardiovascular risk factor management on PD progression.