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Objective To develop and implement a customized toolkit within the electronic medical record (EMR) to standardize care of patients with brain tumors. Patients and Methods We built a customized structured clinical documentation support toolkit to capture standardized data at office visits. We detail the process by which this toolkit was conceptualized and developed. Toolkit development was a physician-led process to determine a work flow and necessary elements to support best practices as defined by the neuro-oncology clinical team. Results We have developed in our EMR system a customized work flow for clinical encounters with neuro-oncology patients. In addition to providing a road map for clinical care by our neuro-oncology team, the toolkit is designed to maximize discrete data capture. Several hundred fields of discrete data are captured through the toolkit in the context of our routine office visits. We describe the characteristics of patients seen at our clinic, the adoption of the toolkit, current initiatives supported by the toolkit, and future applications. Conclusion The EMR can be effectively structured to standardize office visits and improve discrete data capture. This toolkit can be leveraged to support quality improvement and practice-based research initiatives at the point of care in a neuro-oncology practice.

Background We developed and implemented a structured clinical documentation support (SCDS) toolkit within the electronic medical record, to optimize patient care, facilitate documentation, and capture data at office visits in a sleep medicine/neurology clinic for patient care and research collaboration internally and with other centers. Methods To build our SCDS toolkit, physicians met frequently to develop content, define the cohort, select outcome measures, and delineate factors known to modify disease progression. We assigned tasks to the care team and mapped data elements to the progress note. Programmer analysts built and tested the SCDS toolkit, which included several score tests. Auto scored and interpreted tests included the Generalized Anxiety Disorder 7-item, Center for Epidemiological Studies Depression Scale, Epworth Sleepiness Scale, Pittsburgh Sleep Quality Index, Insomnia Severity Index, and the International Restless Legs Syndrome Study Group Rating Scale. The SCDS toolkits also provided clinical decision support (untreated anxiety or depression) and prompted enrollment of patients in a DNA biobank. Results The structured clinical documentation toolkit captures hundreds of fields of discrete data at each office visit. This data can be displayed in tables or graphical form. Best practice advisories within the toolkit alert physicians when a quality improvement opportunity exists. As of May 1, 2019, we have used the toolkit to evaluate 18,105 sleep patients at initial visit. We are also collecting longitudinal data on patients who return for annual visits using the standardized toolkits. We provide a description of our development process and screenshots of our toolkits. Conclusions The electronic medical record can be structured to standardize Sleep Medicine office visits, capture data, and support multicenter quality improvement and practice-based research initiatives for sleep patients at the point of care.

Objective: To use the electronic medical record (EMR) to optimize patient care, facilitate documentation, and support quality improvement and practice-based research in a concussion (mild traumatic brain injury; mTBI) clinic.Methods: We built a customized structured clinical documentation support (SCDS) toolkit for patients in a concussion specialty clinic. The toolkit collected hundreds of fields of discrete, standardized data. Autoscored and interpreted score tests include the Generalized Anxiety Disorder 7-item scale, Center for Epidemiology Studies Depression scale, Insomnia Severity Index, and Glasgow Coma Scale. Additionally, quantitative score measures are related to immediate memory, concentration, and delayed recall. All of this data collection occurred in a standard appointment length.Results: To date, we evaluated 619 patients at an initial office visit after an mTBI. We provided a description of our toolkit development process, and a summary of the data electronically captured using the toolkit.Conclusions: The electronic medical record can be used to effectively structure and standardize care in a concussion clinic. The toolkit supports the delivery of care consistent with Best Practices, provides opportunities for point of care decision support, and writes comprehensive progress notes that can be communicated to other providers.

Genetic risk factors for Parkinson's disease (PD) risk and progression have been identified from genome-wide association studies (GWAS), as well as studies of familial forms of PD, implicating common variants at more than 90 loci and pathogenic or likely pathogenic variants at 16 loci. With the goal of understanding whether genetic variants at these PD-risk loci/genes differentially contribute to individual clinical phenotypic characteristics of PD, we used structured clinical documentation tools within the electronic medical record in an effort to provide a standardized and detailed clinical phenotypic characterization at the point of care in a cohort of 856 PD patients. We analyzed common SNPs identified in previous GWAS studies, as well as low-frequency and rare variants at parkinsonism-associated genes in the MDSgene database for their association with individual clinical characteristics and test scores at baseline assessment in our community-based PD patient cohort: age at onset, disease duration, Unified Parkinson's Disease Rating Scale I-VI, cognitive status, initial and baseline motor and non-motor symptoms, complications of levodopa therapy, comorbidities and family history of neurological disease with one or more than one affected family members. We find that in most cases an individual common PD-risk SNP identified in GWAS is associated with only a single clinical feature or test score, while gene-level tests assessing low-frequency and rare variants reveal genes associated in either a unique or partially overlapping manner with the different clinical features and test scores. Protein-protein interaction network analysis of the identified genes reveals that while some of these genes are members of already identified protein networks others are not. These findings indicate that genetic risk factors for PD differentially affect the phenotypic presentation and that genes associated with PD risk are also differentially associated with individual disease phenotypic characteristics at baseline. These findings raise the intriguing possibility that different SNPs/gene effects impact discrete phenotypic characteristics. Furthermore, they support the hypothesis that different gene and protein-protein interaction networks that underlie PD risk, the PD phenotype, and the neurodegenerative process leading to the disease phenotype, and point to the significance of the genetic background on disease phenotype.

Background: Alzheimer’s disease (AD) and Parkinson’s disease (PD) are the two most prevalent neurodegenerative diseases, both without prevention or cure. The Mediterranean diet (MeDi) may be neuroprotective by modulating gut microbiota. We aimed to assess the effects of adherence to MeDi on the gut microbiota in relation to AD or PD risk. It was our hypothesis that weak adherence to the MeDi, gut microbial dysbiosis, and AD or PD are in a chain of causality. Methods: A search from inception to November 2020 was conducted in PubMed, CINAHL, EMBASE, Web of Science, Global Health, Biological Abstracts, and Grey Literature Report databases. Two searches were conducted: 1) (MeDi or Microbiota) and (PD or AD) and 2) MeDi and microbiota. Inclusion criteria for papers were specified prior to review. Findings: Of 4,672 studies identified, 65 were eligible for inclusion. These studies were divided into five groups: MeDi and AD risk (n=5), MeDi and PD risk (n=2), MeDi and microbial composition or metabolomics (n=21), AD and microbial composition or metabolomics (n=7), and PD and microbial composition or metabolomics (n=30). Adherence to the MeDi was associated with a lower risk of AD, but the results were conflicting for PD risk due to the limited studies. The gut microbiota of MeDi non-adherers shared commonalities with the gut microbiota of AD or PD cases, while the gut microbiota of MeDi adherers was more similar to the gut microbiota of healthy controls than of cases. Eight genera and two species had an inverse relationship with MeDi and AD, and one family, eight genera and three species had an inverse relationship with MeDi and PD. Interpretation: Adherence to the MeDi is associated with a lower risk for AD, and to a lesser extent PD. MeDi, gut microbiota, and neurodegeneration may be causally related. Registration Details: Prospero (CRD42020221170). Funding Information: There was no funding source for this study. Declaration of Interests: None to declare.

Alzheimer’s disease (AD) and AD-related dementias (ADRD) are a class of neurodegenerative diseases affecting about 5.7 million Americans. There is no cure for AD/ADRD. Current interventions have modest effects and focus on attenuating cognitive impairment. Detection of patients at high risk of AD/ADRD is crucial for timely interventions to modify risk factors and primarily prevent cognitive decline and dementia, and thus to enhance the quality of life and reduce health care costs. This study seeks to investigate both knowledge-driven (where domain experts identify useful features) and data-driven (where machine learning models select useful features among all available data elements) approaches for AD/ADRD early prediction using real-world electronic health records (EHR) data from the University of Florida (UF) Health system. We identified a cohort of 59,799 patients and examined four widely used machine learning algorithms following a standard case-control study. We also examined the early prediction of AD/ADRD using patient information 0-years, 1-year, 3-years, and 5-years before the disease onset date. The experimental results showed that models based on the Gradient Boosting Trees (GBT) achieved the best performance for the data-driven approach and the Random Forests (RF) achieved the best performance for the knowledge-driven approach. Among all models, GBT using a data-driven approach achieved the best area under the curve (AUC) score of 0.7976, 0.7192, 0.6985, and 0.6798 for 0, 1, 3, 5-years prediction, respectively. We also examined the top features identified by the machine learning models and compared them with the knowledge-driven features identified by domain experts. Our study demonstrated the feasibility of using electronic health records for the early prediction of AD/ADRD and discovered potential challenges for future investigations.

We studied the long-term risk of depressive and anxiety symptoms in women who underwent bilateral oophorectomy before menopause.We conducted a cohort study among all women residing in Olmsted County, MN, who underwent bilateral oophorectomy before the onset of menopause for a noncancer indication from 1950 through 1987. Each member of the bilateral oophorectomy cohort was matched by age with a referent woman from the same population who had not undergone an oophorectomy. In total, we studied 666 women with bilateral oophorectomy and 673 referent women. Women were followed for a median of 24 years, and depressive and anxiety symptoms were assessed using a structured questionnaire via a direct or proxy telephone interview performed from 2001 through 2006.Women who underwent bilateral oophorectomy before the onset of menopause had an increased risk of depressive symptoms diagnosed by a physician (hazard ratio = 1.54, 95% CI: 1.04-2.26, adjusted for age, education, and type of interview) and of anxiety symptoms (adjusted hazard ratio = 2.29, 95% CI: 1.33-3.95) compared with referent women. The findings remained consistent after excluding depressive or anxiety symptoms that first occurred within 10 years after oophorectomy. The associations were greater with younger age at oophorectomy but did not vary across indications for the oophorectomy. In addition, treatment with estrogen to age 50 years in women who underwent bilateral oophorectomy at younger ages did not modify the risk.Bilateral oophorectomy performed before the onset of menopause is associated with an increased long-term risk of depressive and anxiety symptoms.

Objective To use the electronic medical record (EMR) to optimize patient care, facilitate documentation, and support quality improvement and practice-based research, in a headache specialty clinic. Background Many physicians enter data into the EMR as unstructured free text and not as discrete data. This makes it challenging to use data for quality improvement or research initiatives. Methods We describe the process of building a customized structured clinical documentation support toolkit, specific for patients seen in a headache specialty clinic. The content was developed through frequent physician meetings to reach consensus on elements that define clinical Best Practices. Tasks were assigned to the care team and data mapped to the progress note. Results The toolkit collects hundreds of fields of discrete, standardized data. Auto scored and interpreted score tests include the Generalized Anxiety Disorder 7-item, Center for Epidemiology Studies Depression Scale, Migraine Disability Assessment questionnaire, Insomnia Sleep Index, and Migraine-Specific Quality of Life. We have developed Best Practice Advisories (BPA) and other clinical documentation support tools that alert physicians, when appropriate. As of April 1, 2018, we have used the toolkits at 4346 initial patient visits. We provide screenshots of our toolkits, details of data fields collected, and diagnoses of patients at the initial visit. Conclusions The EMR can be used to effectively structure and standardize headache clinic visits for quality improvement and practice-based research. We are sharing our proprietary toolkit with other clinics as part of the Neurology Practice-Based Research Network. These tools are also facilitating clinical research enrollment and a pragmatic trial of comparative effectiveness at the point-of-care among migraine patients.

ObjectivesTo demonstrate the feasibility of pragmatic clinical trials comparing the effectiveness of treatments using the electronic medical record (EMR) and an adaptive assignment design.MethodsWe have designed and are implementing pragmatic trials at the point-of-care using custom-designed structured clinical documentation support and clinical decision support tools within our physician’s typical EMR workflow. We are applying a subgroup based adaptive design (SUBA) that enriches treatment assignments based on baseline characteristics and prior outcomes. SUBA uses information from a randomization phase (phase 1, equal randomization, 120 patients), to adaptively assign treatments to the remaining participants (at least 300 additional patients total) based on a Bayesian hierarchical model. Enrollment in phase 1 is underway in our neurology clinical practices for 2 separate trials using this method, for migraine and mild cognitive impairment (MCI).ResultsWe are successfully collecting structured data, in the context of the providers’ clinical workflow, necessary to conduct our trials. We are currently enrolling patients in 2 point-of-care trials of non-inferior treatments. As of March 1, 2018, we have enrolled 36% of eligible patients into our migraine study and 63% of eligible patients into our MCI study. Enrollment is ongoing and validation of outcomes has begun.DiscussionThis proof of concept article demonstrates the feasibility of conducting pragmatic trials using the EMR and an adaptive design.ConclusionThe demonstration of successful pragmatic clinical trials based on a customized EMR and adaptive design is an important next step in achieving personalized medicine and provides a framework for future studies of comparative effectiveness.

Objective We describe our experience with routinely capturing and analyzing Mediterranean diet data via structured clinical documentation support tools built into the electronic medical record and describe adherence to the Mediterranean diet in patients at risk for either stroke or dementia in a US neurology clinical practice. Patients and Methods The Mediterranean diet is associated with a reduced risk of stroke and dementia. The Department of Neurology at NorthShore University HealthSystem routinely evaluates patients at initial and annual outpatient visits using structured clinical documentation support (SCDS) tools built into the electronic medical record (EMR). For patient evaluations in our Vascular Neurology and Brain Health subspecialty clinics, SCDS tools in the EMR include the validated 14-item questionnaire for Mediterranean diet adherence (PREvencion con DIeta MEDiterranea [PREDIMED]) that autoscores, auto-interprets, writes to the progress note, and electronically captures data. Our study population includes patients seen at these clinics from July 1, 2015, through November 29, 2017. Results At their initial office visit, 25.5% (95/373) of Brain Health patients scored 10 or more points ("strongly adherent") on the PREDIMED (median, 8; range, 0-14) whereas 6.7% (55/829) of Vascular Neurology patients achieved a score of 10 or more points (median, 6; range, 0-12). By contrast, 34.7% (2586/7447) of individuals in the original PREDIMED cohort were strongly adherent to the Mediterranean diet. Conclusion PREDIMED scores can be electronically captured to tailor nutrition interventions by assessing baseline adherence at the time of their initial neurology clinic visit. Patients in our Midwestern US clinics were weakly adherent to the Mediterranean diet. This suggests a major opportunity for nutrition intervention and education in US neurology clinical practices, toward preserving and improving brain health.

Objective: To determine whether there were differences in clinical outcomes for ioflupane I123 injection (DaTscan) and single photon emission tomography consistent with early Parkinson’s disease (P...

Background: Alzheimer’s disease and aging brain disorders are progressive, often fatal neurodegenerative diseases. Successful aging, modern lifestyles and behaviors have combined to result in an expected epidemic. Risks for these diseases include genetic, medical, and lifestyle factors; over 20 modifiable risks have been reported. Objectives: We aim to primarily prevent Alzheimer’s disease and related disorders through electronic medical record (EMR)-based screening, risk assessments, interventions, and surveillance. Design: We identified modifiable risks; developed human, systems and infrastructural resources; developed interventions; and targeted at-risk groups for the intervention. Setting: A Community Based Health System. Participants: In year one (June 2015 to May 2016), 133 at-risk patients received brain health services with the goal of delaying or preventing Alzheimer’s disease and related disorders. Measurements: We created mechanisms to identify patients at high risk of neurodegenerative disease; EMR-based structured clinical documentation support tools to evaluate risk factors and history; evidence-based interventions to modify risk; and the capacity for annual surveillance, pragmatic trials, and practice-based and genomic research using the EMR. Results: This paper describes our Center for Brain Health, our EMR tools, and our first year of healthy but at-risk patients. Conclusion: We are translating research into primary prevention of Alzheimer’s disease and related disorders in our health system and aim to shift the paradigm in Neurology from brain disease to brain health.

Background and purpose Epilepsy patients are more likely to experience depressive symptoms and cognitive impairment compared to individuals in the general population. As the reasons for this are not definitively known, we sought to determine what factors correlate most strongly with cognition and a screening test for depression in epilepsy patients. Methods Our study population included 379 adult patients diagnosed with epilepsy or seizure in our neurology clinic. We collected detailed demographic and clinical data during patient visits using structured clinical documentation support tools that we have built within our commercial electronic medical records system (Epic), including a depression score (Neurological Disorders Depression Inventory for Epilepsy, NDDIE) and cognition score test measures (specifically in this study, Mini-Mental State Examination [MMSE]). Medication, age, gender, body mass index, duration of epilepsy, seizure frequency, current number of anti-epileptic medications, years of education were assessed in relation to baseline score as well as change in score from initial visit to first annual follow-up. Results Of the analyzed factors, two statistically significant associations were found after correction for multiple testing. Male gender and lower anti-seizure medication count were associated with better mood, as assessed by NDDIE score, at initial visit. Specifically, male gender was associated with a 1.3 decrease in NDDIE and for each additional anti-seizure medication, there was an associated 1.2 increase in NDDIE. Conclusions However, these factors were not associated with change in NDDIE score from initial to first annual follow-up visit. These findings, although interesting, are preliminary. Additionally, these findings were based on a homogenous (mainly Caucasian) clinic-based population and detailed information on previous medication use was lacking. Further work is needed to replicate these findings and to understand any mechanisms that may explain these associations.

Previous studies using verapamil as an adjunct therapy to anti-seizure medications have used doses ranging from 120 to 240mg per day. However, despite showing promising results, there was an increased incidence of side effects. The aim of this study is to assess the efficacy and tolerability of low dose verapamil (20mg p.o. tid) as adjunct therapy to patient's anti-seizure medications irrespective of the type or etiology of the epilepsy. In an open-label pilot study we enrolled 20 adult patients with history of epilepsy who continued to have a minimum of 2 seizures a month despite being on or having tried maximum tolerated doses of 3 or more standard antiepileptic drugs under the supervision of an epileptologist. 10 of the 19 patients (53%) who continued in the study had >50% reduction in seizure frequency. 2 of the patients (10%) had

Gait freezing as a presenting and relatively restricted condition is uncommon but a distinctive disorder. This entity was initially defined as "pure akinesia with gait freezing", and later a neuropathological substrate of progressive supranuclear palsy has been recognized. Limited studies have reported the clinical evolution after presentation, which is important for patient counseling. The objective of this study was to assess the demographic and clinical features, treatment-response, neuroimaging, and evolution of pure akinesia with gait freezing. A retrospective review of patients with this phenotype as previously defined was performed. Patients included had no or minimal limb rigidity and/or bradykinesia and no resting tremor, and all underwent neuroimaging of the brain after onset. Inclusion criteria were met by 30 patients, who were followed up to 21 years after symptom onset. During their course, 28 patients had falls (93 %), 12 patients had dysarthria (40 %), and 13 had handwriting changes (43 %). All patients had progression of their gait disorder over time, but with a variable interval until falls occurred. None of the patients developed vertical gaze palsy or met diagnostic criteria for an alternative parkinsonian disorder. Pure akinesia with gait freezing is a distinctive disorder that can be recognized in the clinic. Despite the previously reported progressive supranuclear palsy-like neuropathology, the clinical course is much less aggressive and disabling than classic Richardson syndrome, although fall risk eventually develops in nearly all patients. Bradykinesia, tremor, and rigidity do not develop, distinguishing pure akinesia with gait freezing from Parkinson's disease and other parkinsonian disorders.

Introduction The MAPT H1 haplotype has been associated with several neurodegenerative diseases. We were interested in exploring the role of MAPT haplotypic variation in risk of dementia with Lewy bodies (DLB). Method We genotyped six MAPT haplotype tagging SNPs and screened 431 clinical DLB cases, 347 pathologically defined high-likelihood DLB cases, and 1049 controls. Result We performed haplotypic association tests and detected an association with the protective H2 haplotype in our combined series (odds ratio [OR] = 0.75). We fine-mapped the locus and identified a relatively rare haplotype, H1G, that is associated with an increased risk of DLB (OR = 3.30, P = .0017). This association was replicated in our pathologically defined series (OR = 2.26, P = .035). Discussion These results support a role for H1 and specifically H1G in susceptibility to DLB. However, the exact functional variant at the locus is still unknown, and additional studies are warranted to fully explain genetic risk of DLB at the MAPT locus.

Background and Purpose: Standardized electronic medical record tools provide an opportunity to efficiently provide care that conforms to Best Practices and supports quality improvement and practice-based research initiatives. Methods: We describe the development of a customized structured clinical documentation “toolkit” that standardizes patient data collection to conform to Best Practices for treating patients with stroke. The toolkit collects patients’ demographic information, relevant score test measures, and captures information on disability, treatment, and outcomes. Results: We describe here our creation and implementation of the toolkits and provide example screenshots. As of August 1, 2018, we have evaluated 2332 patients at an initial visit for a possible stroke. We provide basic descriptive data gathered from the use of the toolkits, demonstrating their utility in collecting patient data in a manner that supports both quality clinical care and research initiatives. Conclusions: We have developed an EMR toolkit to support Best Practices in the care of patients with stroke. We discuss quality improvement projects and current research initiatives using the toolkit. This toolkit is being shared with other Departments of Neurology as part of the Neurology Practice-Based Research Network.

Background In 2017, the International Parkinson and Movement Disorder Society put forward new clinical criteria for the diagnosis of PSP, recognizing diverse PSP phenotypes. In this study, we compared the sensitivity and specificity of the new criteria with the National Institutes of Neurological Disease and Society for Progressive Supranuclear Palsy criteria at different times. Methods Patients with clinical parkinsonism, clinical and/or neuropathological diagnosis of PSP, were identified from the Society for Progressive Supranuclear Palsy brain bank. All patients had neuropathologic diagnoses and detailed clinical examination performed by a neurologist at 1 of the 3 Mayo Clinic sites, in Florida, Arizona, and Minnesota. Clinical symptoms and signs were abstracted retrospectively in a blinded fashion and used to determine whether patients met either diagnostic criterion. Patients were divided into early and late disease stage groups using a 3-year cutoff. Results A total of 129 patients were included, of whom 66 had PSP pathology (51%). The remainder had other neurodegenerative diseases. The overall sensitivity of the International Parkinson and Movement Disorder Society criteria was 87.9%, compared with 45.5% for the National Institutes of Neurological Disease and Society for Progressive Supranuclear Palsy criteria, whereas the specificity of the International Parkinson and Movement Disorder Society probable PSP criteria was 85.7%, compared with 90.5% for the National Institutes of Neurological Disease and Society for Progressive Supranuclear Palsy. Individual patients were noted to have features of multiple PSP phenotypes. Conclusion The International Parkinson and Movement Disorder Society criteria recognize several phenotypes of progressive supranuclear palsy and hence have higher sensitivity than the previous criteria. © 2019 International Parkinson and Movement Disorder Society.

α-Synuclein gene (SNCA) multiplications cause familial parkinsonism and allele-length polymorphisms within the SNCA dinucleotide repeat REP1 increase the risk for developing Parkinson's disease (PD). Since SNCA multiplications increase SNCA expression, and REP1 genotypes that increase the risk of developing PD show increased SNCA expression in cell-culture systems, animal models, and human blood and brain, PD therapies seek to reduce SNCA expression. We conducted an observational study of 1098 PD cases to test the hypothesis that REP1 genotypes correlated with reduced SNCA expression are associated with better motor and cognitive outcomes. We evaluated the association of REP1 genotypes with survival free of Hoehn and Yahr stages 4 or 5 (motor outcome) and of Modified Telephone Interview for Cognitive Status score ≤27 or Alzheimer's Disease Dementia Screening Interview score ≥2 (cognitive outcome). Median disease duration at baseline was 3.3 years and median lag time from baseline to follow-up was 7.8 years. Paradoxically, REP1 genotypes associated with increased risk of developing PD and increased SNCA expression were associated with better motor (HR = 0.87, p = 0.046, covariate-adjusted age-scale analysis; HR = 0.85, p = 0.020, covariate-adjusted time-scale analysis) and cognitive outcomes (HR = 0.90, p = 0.12, covariate-adjusted age-scale analysis; HR = 0.85, p = 0.023, covariate-adjusted time-scale analysis). Our findings raise the possibility that SNCA has a dual, opposing, and time-dependent role. This may have implications for the development of therapies that target SNCA expression.

Objectives: To determine whether alpha-synuclein dinucleotide repeat (REP1) genotypes are associated with survival in Parkinson's disease (PD). Methods: Investigators from the Genetic Epidemiology of Parkinson's Disease Consortium provided REP1 genotypes and baseline and follow-up clinical data for cases. The primary outcome was time to death. Cox proportional hazards regression models were used to assess the association of REP1 genotypes with survival. Results: Twenty-one sites contributed data for 6,154 cases. There was no significant association between alpha-synuclein REP1 genotypes and survival in PD. However, there was a significant association between REP1 genotypes and age at onset of PD (hazard ratio: 1.06; 95% confidence interval: 1.01-1.10; P value = 0.01). Conclusions: In our large consortium study, alpha-synuclein REP1 genotypes were not associated with survival in PD. Further studies of alpha-synuclein's role in disease progression and long-term outcomes are needed. (C) 2014 International Parkinson and Movement Disorder Society

BackgroundVariants within the leucine-rich repeat kinase 2 gene are recognized as the most frequent genetic cause of Parkinson's disease. Leucine-rich repeat kinase 2 variation related to disease susceptibility displays many features that reflect the nature of complex, late-onset sporadic disorders like Parkinson's disease. MethodsThe Genetic Epidemiology of Parkinson's Disease Consortium recently performed the largest genetic association study for variants in the leucine-rich repeat kinase 2 gene across 23 different sites in 15 countries. ResultsHerein, we detail the allele frequencies for the novel risk factors (p.A419V and p.M1646T) and the protective haplotype (p.N551K-R1398H-K1423K) nominated in the original publication. Simple population allele frequencies not only can provide insight into the clinical relevance of specific variants but also can help genetically define patient groups. ConclusionsEstablishing individual patient-based genomic susceptibility profiles that incorporate both risk factors and protective factors will determine future diagnostic and treatment strategies. (c) 2013 International Parkinson and Movement Disorder Society (Less)

SummaryObjective Using the electronic medical record (EMR) to capture structured clinical data at the point of care would be a practical way to support quality improvement and practice-based research in epilepsy. Methods We describe our stepwise process for building structured clinical documentation support tools in the EMR that define best practices in epilepsy, and we describe how we incorporated these toolkits into our clinical workflow. Results These tools write notes and capture hundreds of fields of data including several score tests: Generalized Anxiety Disorder-7 items, Neurological Disorders Depression Inventory for Epilepsy, Epworth Sleepiness Scale, Quality of Life in Epilepsy–10 items, Montreal Cognitive Assessment/Short Test of Mental Status, and Medical Research Council Prognostic Index. The tools summarize brain imaging, blood laboratory, and electroencephalography results, and document neuromodulation treatments. The tools provide Best Practices Advisories and other clinical decision support when appropriate. The tools prompt enrollment in a DNA biobanking study. We have thus far enrolled 231 patients for initial visits and are starting our first annual follow-up visits and provide a brief description of our cohort. Significance We are sharing these EMR tools and captured data with other epilepsy clinics as part of a Neurology Practice Based Research Network, and are using the tools to conduct pragmatic trials using subgroup-based adaptive designs.

A recent study MacLeod et al. has shown that an interaction between variants at the LRRK2 and PARK16 loci influences risk of development of Parkinson's disease (PD). Our study examines the proposed interaction between LRRK2 and PARK16 variants in modifying PD risk using a large multicenter series of PD patients (7715) and controls (8261) from sites participating in the Genetic Epidemiology of Parkinson's Disease Consortium. Our data does not support a strong direct interaction between LRRK2 and PARK16 variants; however, given the role of retromer and lysosomal pathways in PD, further studies are warranted. (C) 2016 Elsevier Inc. All rights reserved.

Background Two recent studies identified a mutation (p.Asp620Asn) in the vacuolar protein sorting 35 gene as a cause for an autosomal dominant form of Parkinson disease. Although additional missense variants were described, their pathogenic role yet remains inconclusive. Methods and results We performed the largest multi-center study to ascertain the frequency and pathogenicity of the reported vacuolar protein sorting 35 gene variants in more than 15,000 individuals worldwide. p.Asp620Asn was detected in 5 familial and 2 sporadic PD cases and not in healthy controls, p.Leu774Met in 6 cases and 1 control, p.Gly51Ser in 3 cases and 2 controls. Overall analyses did not reveal any significant increased risk for p.Leu774Met and p.Gly51Ser in our cohort. Conclusions Our study apart from identifying the p. Asp620Asn variant in familial cases also identified it in idiopathic Parkinson disease cases, and thus provides genetic evidence for a role of p.Asp620Asn in Parkinson disease in different populations worldwide.

Lewy pathology occurs in 8–17% of neurologically normal people age >60, termed incidental Lewy body disease (iLBD). It is often assumed to represent preclinical Parkinson disease (PD). However, some iLBD cases have diffuse pathology inconsistent with preclinical PD. We analyzed iLBD cases (α-synuclein immunohistochemistry) using the Braak PD staging scheme and determined if some had a neuropathological pattern suggestive of preclinical dementia with Lewy bodies (DLB). Of the 235 brains examined, 34 had iLBD (14.5%) and all but one could be assigned a Braak PD stage. The distribution of α-synuclein pathology in the 33 cases fell into three patterns: (1) diffuse cortical and subcortical α-synuclein pathology; (2) no cortical α-synuclein pathology, but a caudal-to-rostral ascending pattern, primarily involving brainstem; and (3) intermediate between these two categories. Also, 6/33 cases failed to follow the pattern of contiguous spread proposed by Braak. These findings suggest dichotomy in the distribution of iLBD: some cases fit the Braak ascending scheme, conceptually consistent with preclinical PD, whereas others displayed prominent cortical involvement that might represent preclinical DLB.

The purpose of this paper is to provide the rationale for therapeutic silencing of the alpha-synuclein gene (SNCA) in Parkinson’s disease (PD). The paper reviews the public health significance of PD; the causal links between rare SNCA variants and familial PD; the association of common SNCA variants and PD susceptibility; the association of SNCA variants also with age at onset and motor and cognitive outcomes in PD; therapeutic strategies targeting SNCA in PD; and preliminary findings and considerations on small interfering RNA-based therapies and PD.

Incidence rates of Parkinson's disease are higher in men than in women at all ages, and these differences may be a result of the neuroprotective effects of estrogen on the nigrostriatal pathway. We investigated the association of common variants in 4 estrogen-related genes with Parkinson's disease. Tagging single-nucleotide polymorphisms in the CYP19A1, ESR1, ESR2, and PRDM2 genes were selected from the International Haplotype Map and genotyped in 1103 Parkinson's disease cases from the upper Midwest of the United States and in 1103 individually matched controls (654 unaffected siblings, and 449 unrelated controls from the same region). Of 137 informative single-nucleotide polymorphisms, 2 PRDM2 single-nucleotide polymorphisms were significantly associated with an increased risk of Parkinson's disease at the Bonferroni-corrected significance level of 0.0004 (rs2744690: OR, 1.54; SE(logOR), .109; 99.96% CI, 1.05-2.26; uncorrected P = .0001; rs2744687: OR, 1.53; SE(logOR), .113; 99.96% CI, 1.03-2.29, uncorrected P = .0002); the association was significant in the women-only stratum but not in the men-only stratum. An additional 6 single-nucleotide polymorphisms in PRDM2, 2 in ESR1, 1 in ESR2, and 1 in CYP19A1 had significant P values in the overall sample before Bonferroni correction. None of the single-nucleotide polymorphisms were significantly associated with age at onset of Parkinson's disease after Bonferroni correction. Our results confirm the association of PRDM2 variants with Parkinson's disease susceptibility, especially in women.

Background Many physicians enter data into the electronic medical record (EMR) as unstructured free text and not as discrete data, making it challenging to use for quality improvement or research initiatives. Objectives The objective of this research paper was to develop and implement a structured clinical documentation support (SCDS) toolkit within the EMR to facilitate quality initiatives and practice-based research in a multiple sclerosis (MS) practice. Methods We built customized EMR toolkits to capture standardized data at office visits. Content was determined through physician consensus on necessary elements to support best practices in treating patients with demyelinating disorders. We also developed CDS tools and best practice advisories within the toolkits to alert physicians when a quality improvement opportunity exists, including enrollment into our DNA biobanking study at the point of care. Results We have used the toolkit to evaluate 541 MS patients in our clinic and begun collecting longitudinal data on patients who return for annual visits. We provide a description and example screenshots of our toolkits, and a brief description of our cohort to date. Conclusions The EMR can be effectively structured to standardize MS clinic office visits, capture data, and support quality improvement and practice-based research initiatives at the point of care.

We studied the association of three personality traits related to neuroticism with the subsequent risk of Parkinson's disease (PD) using a historical cohort study. We included 7,216 subjects who resided within the 120-mile radius centered in Rochester, MN, at the time they completed the Minnesota Multiphasic Personality Inventory (MMPI) for research at the Mayo Clinic from 1962 to 1965. We considered three MMPI personality scales (pessimistic, anxious, and depressive traits). A total of 6,822 subjects (94.5%) were followed over four decades either actively or passively. During follow-up, 227 subjects developed parkinsonism (156 developed PD). An anxious personality was associated with an increased risk of PD [hazard ratio (HR), 1.63; 95% confidence interval (CI), 1.16-2.27]. A pessimistic personality trait was also associated with an increased risk of PD but only in men (HR = 1.92; 95% CI = 1.20-3.07). By contrast, a depressive trait was not associated with increased risk. Analyses combining scores from the three personality scales into a composite neuroticism score showed an association of neuroticism with PD (HR = 1.54; 95% CI = 1.10-2.16). The association with neuroticism remained significant even when the MMPI was administered early in life (ages 20-39 years). By contrast, none of the three personality traits was associated with the risk of non-PD types of parkinsonism grouped together. Our long-term historical cohort study suggests that an anxious personality trait may predict an increased risk of PD developing many years later.

Objective: Parkinson disease (PD) may affect the autonomic nervous system and may cause constipation; however, few studies have explored constipation preceding the motor onset of PD. We investigated constipation preceding PD using a case-control study design in a population-based sample. Methods: Using the medical records-linkage system of the Rochester Epidemiology Project, we identified 196 subjects who developed PD in Olmsted County, MN, from 1976 through 1995. Each incident case was matched by age (±1 year) and sex to a general population control. We reviewed the complete medical records of cases and controls in the medical records-linkage system to ascertain the occurrence of constipation preceding the onset of PD (or index year). Results: Constipation preceding PD or the index year was more common in cases than in controls (odds ratio [OR] 2.48; 95% confidence interval [CI] 1.49 to 4.11; p = 0.0005). This association remained significant after adjusting for smoking and coffee consumption (ever vs never), and after excluding constipation possibly induced by drugs. In addition, the association remained significant in analyses restricted to constipation documented 20 or more years before the onset of motor symptoms of PD. Although the association was stronger in women than in men and in patients with PD with rest tremor compared with patients with PD without rest tremor, these differences were not significant. Conclusions: Our findings suggest that constipation occurring as early as 20 or more years before the onset of motor symptoms is associated with an increased risk of Parkinson disease.

We investigated the association of Bell's palsy (BP) with the subsequent risk of Parkinson's disease (PD) using a case-control study design. We matched 196 incident cases of PD in Olmsted County, MN, to 196 general population controls with same age (+/-1 year) and sex, and we reviewed the complete medical records of cases and controls in a medical records-linkage system to detect BP. Six of the 196 patients with PD and none of the 196 controls were diagnosed with BP before PD (exact binomial probability, P = 0.02). The median age at occurrence of BP was 49.5 years (range, 15-84 years) and the median time between BP and the onset of PD was 27.5 years (range, 2-54 years). The findings were similar using a standardized incidence ratio (SIR) approach, but were not statistically significant. This initial association between BP and PD awaits replication.

In the Mayo Clinic Cohort Study of Oophorectomy and Aging, women who had both ovaries removed before reaching natural menopause experienced a long-term increased risk of parkinsonism, cognitive impairment or dementia, and depressive and anxiety symptoms. Here, we discuss five possible mechanistic interpretations of the observed associations; first, the associations may be non-causal because they result from the confounding effect of genetic variants or of other risk factors; second, the associations may be mediated by an abrupt reduction in levels of circulating estrogen; third, the associations may be mediated by an abrupt reduction in levels of circulating progesterone or testosterone; fourth, the associations may be mediated by an increased release of gonadotropins by the pituitary gland; and fifth, genetic variants may modify the hormonal effects of bilateral oophorectomy through simple or more complex interactions. Results from other studies are cited as evidence for or against each possible mechanism. These putative causal mechanisms are probably intertwined, and their clarification is a research priority.

An inverse association between coffee and Parkinson's disease (PD) has been reported. However, it remains uncertain why some but not all coffee drinkers are less susceptible to PD. We considered the possibility of a pharmaco-genetic effect. In our study, we included 1,208 subjects (446 case-unaffected sibling pairs and 158 case-unrelated control pairs) recruited from an ongoing study of the molecular epidemiology of PD in the Upper Midwest (USA). We collected information on lifetime coffee drinking and we studied two genes: ADORA2A, which encodes the major receptor activity of caffeine in the brain (variants rs5751876 and rs3032740), and CYP1A2, which encodes the major rate-limiting step of caffeine metabolism (variants rs35694136 and rs762551). We did not observe significant associations of coffee drinking or of the genetic variants with PD susceptibility, either independently or jointly, in the sample overall and in most strata. Our study neither supports the hypothesis that coffee protects against PD nor provides evidence for a pharmacogenetic effect.

Background: The evidence for a neuroprotective effect of estrogen in women remains controversial. Objective: We studied the long-term risk of parkinsonism and of cognitive impairment or dementia in women who underwent oophorectomy before menopause. Methods: We conducted a historical cohort study among all women residing in Olmsted County, Minn., USA, who underwent unilateral or bilateral oophorectomy before the onset of menopause for a noncancer indication from 1950 through 1987. Each member of the oophorectomy cohort was matched by age to a referent woman from the same population who had not undergone oophorectomy. In total, we studied 1,252 women with unilateral oophorectomy, 1,075 women with bilateral oophorectomy, and 2,368 referent women. Women were followed for a median of 25–30 years. Parkinsonism was assessed using screening and examination, through a medical records- linkage system, and through death certificates. Cognitive status was assessed using a structured questionnaire via a direct or proxy telephone interview. Results: The risk of parkinsonism and of cognitive impairment or dementia increased following oophorectomy. In particular, we observed significant linear trends of increasing risk for either outcome with younger age at oophorectomy. Conclusion: Our findings, combined with previous laboratory and epidemiologic findings, suggest that estrogen may have an age-dependent neuroprotective effect.

There is increasing laboratory evidence that estrogen has neuroprotective effects that may include improved synapse formation, increased cerebral blood flow and glucose metabolism, antioxidant activity, and reduced deposition of β-amyloid in the brain. Clinical and epidemiological evidence, however, has lagged behind. It could well be that there is a critical age window within which neuroprotective effects express themselves. This study examined the association between oophorectomy, performed before the start of menopause for reasons unrelated to tumor, with the risk of subsequent cognitive impairment or dementia as disclosed by a modified form of the Telephone Interview for Cognitive Status. The final study groups included 813 women having unilateral oophorectomy; 676 having bilateral oophorectomy; and 1472 referent women matched for age with the surgical groups. Compared to referent women, those undergoing unilateral or bilateral oophorectomy had an increased risk of cognitive impairment or dementia. The hazard ratio was 1.46 and the 95% confidence interval 1.13-1.90 after adjusting for education and a history of depression. The risk of cognitive dysfunction or dementia increased as the age at the time of oophorectomy declined, and was significantly increased when oophorectomy was done before age 49 years. The findings were independent of the indication for oophorectomy, and were similar following unilateral and bilateral oophorectomy. Oophorectomy-either unilateral or bilateral-appears to carry with it an increased risk of cognitive impairment or dementia when performed before the start of menopause. This study is one of the first to support the idea of a critical age window for protective effects of estrogen on the brain. The findings encourage a reassessment of prophylactic oophorectomy in premenopausal women and also of estrogen therapy following oophorectomy.

In multiple system atrophy (MSA), increased venous compliance with excessive venous pooling is assumed to be a major contributor to orthostatic hypotension (OH); however, venous compliance has never been assessed in MSA patients. We evaluated the severity and distribution of adrenergic, cardiovagal, and sudomotor failure in 11 patients with probable MSA, 14 age- and sex-matched control subjects, and 8 patients with Parkinson's disease (PD) but not OH. Calf venous compliance, venous filling, and capillary filtration were measured using calf plethysmography. The response to the directly acting α-adrenergic stimulation (10 mg midodrine) on calf venous compliance was additionally evaluated. Contrary to our hypothesis, pressure-volume curves in the legs of MSA patients were flatter than in PD patients ( P < 0.05) or controls ( P < 0.001); this indicated reduced calf venous compliance in MSA. The MSA group had reduced venous filling compared with control ( P < 0.001) or PD subjects ( P < 0.001) but had a normal capillary filtration rate ( P = 0.73). Direct α-adrenergic stimulation resulted in a slight but significant reduction of calf venous compliance in controls ( P = 0.001) and PD subjects ( P < 0.001) but not in the MSA group. The compliance change in MSA significantly regressed with autonomic failure (composite autonomic severity scale, r2 = 0.56) but not with parkinsonism (Unified MSA Rating Scale, r2 = 0.12). Our data indicate that MSA patients with chronic OH have reduced, rather than increased, venous compliance in the lower leg. We postulate that chronic venous distension that is associated with OH results in structural remodeling of veins, leading to reduced compliance, a change which may protect patients against orthostatic stress.

The Human Genome Epidemiology Network (HuGENet) recently launched a global network of consortia working on human genome epidemiology. This Network of Investigator Networks aims to create a resource to share information, offer methodologic support, generate inclusive overviews of studies conducted in specific fields, and to facilitate rapid confirmation of findings. In October 2005, HuGENet brought together representatives from established and emerging networks in order to share their experiences at a workshop in Cambridge, United Kingdom. In advance of the meeting, a qualitative questionnaire was distributed to workshop participants. The questionnaire elicited information on experiences and practices in building and maintaining consortia. This chapter reports on the numerous challenges and their possible solutions as identified by the workshop participants, as well as new opportunities offered by the network approach to genetic and genomic epidemiology.

We investigated the association between number of children and Parkinson's disease (PD) in two independent studies. In a case-control study, we identified all subjects who developed PD in Olmsted County, MN, from 1976 through 1995, and matched them individually by age (+/-1 year) and sex to population controls (193 cases and 193 controls). The replication study was a population-based cohort study of 6,341 subjects from Rotterdam, the Netherlands (2,610 men). In the Olmsted County study, men who fathered at least one child had an increased risk of PD (unadjusted OR, 2.7; 95% CI, 1.2-6.1; P = 0.02), and the risk increased with increasing number of children. The findings in women were not significant. In the Rotterdam Study, the risk of PD increased significantly with increasing number of children in men (test for linear trend, unadjusted; P = 0.04), but not in women. The findings from both studies remained consistent in direction but reduced in magnitude of the association, and lost significance after simultaneous adjustment for education, cigarette smoking, alcohol consumption, and coffee consumption. The independent replication in two distinct populations and using different epidemiologic study designs may suggest a link between the number of children and PD restricted to men.

Genetic factors and environmental exposures, including pesticides, contribute to the risk of Parkinson's disease (PD). There have been few studies of gene and pesticide exposure interactions in PD, and all of the prior studies used a candidate gene approach.We performed the first genome-wide gene-environment interaction analysis of pesticide exposure and risk of Parkinson's disease. Analyses were performed using data on700,000 single nucleotide polymorphisms (SNPs) in 364 discordant sibling pairs. In addition to testing for SNP-pesticide interaction effects, we also performed exploratory analyses of gene-pesticide interactions at the gene level.None of the gene-environment interaction results were significant after genome-wide correction for multiple testing (α = 1.5E-07 for SNP-level tests; α = 2.1E-06 for gene-level tests). Top results in the SNP-level tests provided suggestive evidence (P 5.0E-06) that the effect of pesticide exposure on PD risk may be modified by SNPs in the ERCC6L2 gene (P = 2.4E-06), which was also supported by suggestive evidence in the gene-level analysis (P = 4.7E-05). None of the candidate genes assessed in prior studies of gene-pesticide interactions reached statistical support in this genome-wide screen.Although no significant interactions were identified, several of the genes with suggestive evidence of gene-environment interaction effects have biological plausibility for PD risk. Further investigation of the role of those genes in PD risk, particularly in the context of pesticide exposure, in large and carefully recruited samples is warranted.

We describe quality improvement and practice-based research using the electronic medical record (EMR) in a community health system–based department of neurology. Our care transformation initiative targets 10 neurologic disorders (brain tumors, epilepsy, migraine, memory disorders, mild traumatic brain injury, multiple sclerosis, neuropathy, Parkinson disease, restless legs syndrome, and stroke) and brain health (risk assessments and interventions to prevent Alzheimer disease and related disorders in targeted populations). Our informatics methods include building and implementing structured clinical documentation support tools in the EMR; electronic data capture; enrollment, data quality, and descriptive reports; quality improvement projects; clinical decision support tools; subgroup-based adaptive assignments and pragmatic trials; and DNA biobanking. We are sharing EMR tools and deidentified data with other departments toward the creation of a Neurology Practice-Based Research Network. We discuss practical points to assist other clinical practices to make quality improvements and practice-based research in neurology using the EMR a reality.

Objective: To assess the importance of MAPT variant p.A152T in the risk of synucleinopathies. Methods: In this case-control study, we screened a large global series of patients and controls, and assessed associations between p.A152T and disease risk. We included 3,229 patients with clinical Parkinson disease (PD), 442 with clinical dementia with Lewy bodies (DLB), 181 with multiple system atrophy (MSA), 832 with pathologically confirmed Lewy body disease (LBD), and 2,456 healthy controls. Results: The minor allele frequencies (MAF) in clinical PD cases (0.28%) and in controls (0.2%) were not found to be significantly different (odds ratio [OR] 1.37, 95% confidence interval [CI] 0.63-2.98, p 0.42). However, a significant association was observed with clinical DLB (MAF 0.68%, OR 5.76, 95% CI 1.62-20.51, p 0.007) and LBD (MAF 0.42%, OR 3.55, 95% CI 1.04-12.17, p 0.04). Additionally, p.A152T was more common in patients with MSA compared to controls (MAF 0.55%, OR 4.68, 95% CI 0.85-25.72, p 0.08) but this was not statistically significant and therefore should be interpreted with caution. Conclusions: Overall, our findings suggest that MAPT p.A152T is a rare low penetrance variant likely associated with DLB that may be influenced by coexisting LBD and AD pathology. Given the rare nature of the variant, further studies with greater sample size are warranted and will help to fully explain the role of p.A152T in the pathogenesis of the synucleinopathies. © 2015 American Academy of Neurology.

Parkinson disease (PD) is associated with a clinical course of variable duration, severity, and a combination of motor and non-motor features. Recent PD research has focused primarily on etiology rather than clinical progression and long-term outcomes. For the PD patient, caregivers, and clinicians, information on expected clinical progression and long-term outcomes is of great importance. Today, it remains largely unknown what factors influence long-term clinical progression and outcomes in PD; recent data indicate that the factors that increase the risk to develop PD differ, at least partly, from those that accelerate clinical progression and lead to worse outcomes. Prospective studies will be required to identify factors that influence progression and outcome. We suggest that data for such studies is collected during routine office visits in order to guarantee high external validity of such research. We report here the results of a consensus meeting of international movement disorder experts from the Genetic Epidemiology of Parkinson's Disease (GEO-PD) consortium, who convened to define which long-term outcomes are of interest to patients, caregivers and clinicians, and what is presently known about environmental or genetic factors influencing clinical progression or long-term outcomes in PD. We propose a panel of rating scales that collects a significant amount of phenotypic information, can be performed in the routine office visit and allows international standardization. Research into the progression and long-term outcomes of PD aims at providing individual prognostic information early, adapting treatment choices, and taking specific measures to provide care optimized to the individual patient's needs.

This study investigated the reliability of self-reported ancestry by comparing the interview responses of probands and their siblings. A total of 546 sibling pairs were ascertained in a family-based study of susceptibility genes for Parkinson's disease and asked to identify maternal and paternal countries of origin. Probands were recruited prospectively from the Department of Neurology of the Mayo Clinic in Rochester, Minnesota, from June 1, 1996, through May 31, 2005. Probands resided within Minnesota or one of the four surrounding states (Wisconsin, Iowa, South Dakota, North Dakota). Only 49 percent of these sibling pairs, primarily Caucasian, agreed completely on the countries of origin of both parents. The agreement increased to 68 percent when named countries were postcoded into six population genetic clusters (as previously defined by microsatellite markers). Self-reported ancestry may not be a reliable method to reduce the possible impact of population stratification in genetic association studies of outbred populations, such as in the United States.

In an inception cohort of 196 Olmsted County, Minnesota, residents with Parkinson's disease (PD) first recognized in 1976 to 1995, we tested whether the increased risk of bone fractures is associated with concomitant dementia. Using the data resources of the Rochester Epidemiology Project, information about PD, dementia, other clinical risk factors for fracture and fracture events was obtained from review of complete inpatient and outpatient medical records spanning each subject's residence in the community. Compared to an equal number of age- and sex-matched non-PD referent subjects from the community, PD patients were at a 2.2-fold increased risk of fractures generally and a 3.2-fold greater risk of hip fractures specifically. Adjusting for age, the independent predictors of overall fracture risk in the PD subjects included female sex (hazard ratio [HR] 1.6; 95% confidence interval [CI], 1.1-2.3), dementia (HR, 1.6; 95% CI, 1.1-2.4) and chronic depression, which was associated with a reduced risk (HR, 0.4; 95% CI, 0.2-0.8). Hip fractures were predicted by dementia (HR, 2.2; 95% CI, 1.2-4.1). The increased fracture risk in patients with PD is not entirely explained by concomitant dementia, and additional study is needed to determine the relative contributions to fracture risk of falls versus bone loss in these patients.