Online education for safer opioid prescribing in hospitals-lessons learnt from the Opioid Use Change (OUCh) project.

BACKGROUND: Opioids are often required for acute inpatient pain relief but lack of knowledge about common and less common long-term side effects can lead to inappropriate discharge prescribing. There are few validated educational tools available for junior prescribers on hospital wards. Education around opioid prescribing and deprescribing remains limited in the undergraduate curriculum and yet almost all controlled drug prescribing in hospitals is done by junior doctors. METHODS: A 5-minute video was developed with iterative feedback from medical students, junior prescribers, pain specialists, primary care educational leads, and a patient who had developed opioid addiction after hospital prescribing. It explained the need for clear stop dates on discharge summaries and the range of opioid side effects. It also highlighted the hospital admission as an opportunity to reduce inappropriate high-dose opioids. A short knowledge-based quiz before and after viewing the video was used to evaluate the impact on and change in knowledge and confidence around opioid prescribing. This tool was designed to be used entirely online to allow delivery within existing mandatory training. RESULTS: Feedback was positive and showed that knowledge of side effects significantly increased but also contacts with ward pharmacists and the acute pain team increased. Junior doctors highlighted that the undergraduate curriculum did little to prepare them for prescription addiction and that pharmacy and senior support was needed to support any changes in longer-term, high-dose opioids. CONCLUSIONS: This short educational video improved knowledge of safe opioid prescribing and could be incorporated within wider opioid education in UK healthcare.

Sleep disorders in Lewy body dementia: Mechanisms, clinical relevance, and unanswered questions.

In Lewy body dementia (LBD), disturbances of sleep and/or arousal including insomnia, excessive daytime sleepiness, rapid eye movement (REM) sleep behavior disorder, obstructive sleep apnea, and restless leg syndrome are common. These disorders can each exert a significant negative impact on both patient and caregiver quality of life; however, their etiology is poorly understood. Little guidance is available for assessing and managing sleep disorders in LBD, and they remain under-diagnosed and under-treated. This review aims to (1) describe the specific sleep disorders which occur in LBD, considering their putative or potential mechanisms; (2) describe the history and diagnostic process for these disorders in LBD; and (3) summarize current evidence for their management in LBD and consider some of the ongoing and unanswered questions in this field and future research directions.

The relationship between physical activity, BMI, circadian rhythm, and sleep with cognition in bipolar disorder.

BACKGROUND: Cognitive deficits affect a significant proportion of patients with bipolar disorder (BD). Problems with sustained attention have been found independent of mood state and the causes are unclear. We aimed to investigate whether physical parameters such as activity levels, sleep, and body mass index (BMI) may be contributing factors. METHODS: Forty-six patients with BD and 42 controls completed a battery of neuropsychological tests and wore a triaxial accelerometer for 21 days which collected information on physical activity, sleep, and circadian rhythm. Ex-Gaussian analyses were used to characterise reaction time distributions. We used hierarchical regression analyses to examine whether physical activity, BMI, circadian rhythm, and sleep predicted variance in the performance of cognitive tasks. RESULTS: Neither physical activity, BMI, nor circadian rhythm predicted significant variance on any of the cognitive tasks. However, the presence of a sleep abnormality significantly predicted a higher intra-individual variability of the reaction time distributions on the Attention Network Task. CONCLUSIONS: This study suggests that there is an association between sleep abnormalities and cognition in BD, with little or no relationship with physical activity, BMI, and circadian rhythm.

Longitudinal Studies of Sleep Disturbances in Parkinson's Disease.

PURPOSE OF REVIEW: Sleep disorders are among the most common non-motor symptoms in Parkinson's disease (PD). Recent longitudinal studies of sleep in PD have utilized validated sleep questionnaires and video-polysomnography performed over multiple time points. This review summarizes existing longitudinal studies focusing on the prevalence, associations, and changes of sleep disorders in PD over time, as well as the methodologies used in these studies. RECENT FINDINGS: Fifty-three longitudinal studies of sleep in PD were identified: excessive daytime sleepiness, insomnia, obstructive sleep apnea, rapid eye movement sleep behavior disorder (RBD), restless legs syndrome, and shift work disorder were studied in addition to other studies that had focused on either multiple sleep disorders or broadly on sleep disorders as a whole. The prevalence of sleep disorders increases over time and are associated particularly with non-motor features of disease. RBD is now considered an established prodromal feature of PD, but other sleep disorders do not clearly increase risk of subsequent PD. Further work is necessary to determine if treatment of sleep disorders in PD alters disease symptom and their progression or reduces PD risk. Longitudinal studies of sleep in PD have demonstrated a high prevalence of sleep disorders that are associated with non-motor features of PD which can increase over time. More work is necessary to determine if treatment of sleep disorders can alter the course of PD.

Delivering an advice and guidance service in neurology.

It is increasingly common for secondary care to provide advice to primary care without an outpatient appointment. Even before the increased telemedicine during COVID-19, many hospital services gave advice alone for some referrals, yet there are few published data about patient outcomes. Does advice and guidance alter outpatient numbers or simply mean that patients are seen later? Which neurological conditions can we manage at a distance? Do complaints increase from either primary care or patients? Do clinics become more complex and time consuming? Our department has developed an advice and guidance service embedded within the English electronic referral system since 2017, allowing detailed analysis of the outcome of 6500 patients over 2.5 years. We suggest ways to set up and run a neurology advice and guidance service, looking at the potential benefits and the barriers.

Sleep disturbance in movement disorders: insights, treatments and challenges.

Sleep and circadian rhythm disturbances are central features of many movement disorders, exacerbating motor and non-motor symptoms and impairing quality of life. Understanding these disturbances to sleep is clinically important and may further our understanding of the underlying movement disorder. This review evaluates the current anatomical and neurochemical understanding of normal sleep and the recognised primary sleep disorders. In addition, we undertook a systematic review of the evidence for disruption to sleep across multiple movement disorders. Rapid eye movement sleep behaviour disorder has emerged as the most reliable prodromal biomarker for the alpha synucleinopathies, including Parkinson's disease and multiple system atrophy, often preceding motor symptom onset by several years. Abnormal sleep has also been described for many other movement disorders, but further evidence is needed to determine whether this is a primary or secondary phenotypic component of the underlying condition. Medication used in the treatment of motor symptoms also affects sleep and can aggravate or cause certain sleep disorders. Within the context of movement disorders, there is also some suggestion of a shared underlying mechanism for motor and sleep pathophysiology, with evidence implicating thalamic and brainstem structures and monoaminergic neurotransmission. This review highlights the need for an understanding of normal and abnormal sleep within the movement disorder clinic, an ability to screen for specific causes of poor sleep and to treat sleep disturbance to improve quality of life. Key sleep disorders also act as important biomarkers and have implications in diagnosis, prognosis and the development of future therapies.

Active travelling to school is not associated with increased total daily physical activity levels, or reduced obesity and cardiovascular/pulmonary health parameters in 10-12-year olds: a cross-sectional cohort study.

BACKGROUND/OBJECTIVES: Childhood obesity has increased enormously. Several lifestyle factors have been implicated, including decreased physical activity, partially involving a decline in active travel to school. We aimed to establish the association between school transport mode and physical activity levels of primary 6 and 7 children (aged 10-12). Secondary outcomes were body mass index standard deviation scores, blood pressure levels and lung function. SUBJECTS/METHODS: A cross-sectional study was conducted with a total number of 432 children from three primary schools in North East Scotland. Actigraph accelerometers were used to provide objective measures of physical activity. Ninety-two children in primary 6 and 90 children in primary 7 (40 in common) had adequate data. Modes of transport to school were assessed by a questionnaire. Two hundred and seventeen children in primary 6 and one hundred and sixty-five in primary 7 returned adequate questionnaires. Children who used active transport modes for >70% of their journeys to school over the week were coded as active travellers and <30% were coded as passive travellers. All children also had height, weight, blood pressure levels and lung function measured. RESULTS: Children who lived further away from school, and in more expensive properties were more likely to travel passively to school. Actively commuting children (70% walking) had significantly higher activity levels than passive commuters during the 30 min that encompassed their journey to and from school. However, there were no significant differences between active and passive school travellers in total daily physical activity, BMI SDS, and both systolic and diastolic blood pressure and lung function. CONCLUSIONS: There was no evidence that more days of active travel to school had a significant influence on total physical activity, obesity and related health parameters. Public health interventions promoting active travel to school may have limited success in quelling the childhood obesity epidemic.

Niemann-Pick type C: contemporary diagnosis and treatment of a classical disorder.

Niemann-Pick type C is an uncommon neurodegenerative lysosomal storage disorder that can cause a progressive neuropsychiatric syndrome associated with supranuclear vertical gaze palsy and a movement disorder. There have been recent developments in testing that make diagnosis easier and new therapies that aim to stabilise the disease process. A new biochemical test to measure serum cholesterol metabolites supersedes the skin biopsy and is practical and robust. It is treatable with miglustat, a drug that inhibits glycosphingolipid synthesis. We describe a patient, aged 22 years, with juvenile-onset Niemann-Pick type C who presented with seizures and a label of 'cerebral palsy'. We describe the approach to this syndrome in general, and highlight the classical features and red flags that should alert a neurologist to this treatable condition.

Depressive symptoms are associated with daytime sleepiness and subjective sleep quality in dementia with Lewy bodies.

OBJECTIVE: Sleep problems and depression are common symptoms in dementia with Lewy bodies (DLB), where patients typically experience subjectively poor sleep quality, fatigue and excessive daytime sleepiness. However, whilst sleep disturbances have been linked to depression, this relationship has not received much attention in DLB. The present cross-sectional study addresses this by examining whether depressive symptoms are specifically associated with subjective sleep quality and daytime sleepiness in DLB, and by examining other contributory factors. METHODS: DLB patients (n = 32) completed the Pittsburgh Sleep Quality Index (PSQI), Epworth Sleepiness Scale (ESS) and the 15-item Geriatric Depression Scale (GDS-15). Motor and cognitive functioning was also assessed. Pearson correlations were used to assess the relationship between GDS-15, ESS and PSQI scores. RESULTS: GDS-15 scores were positively associated with both ESS (r = 0.51, p < 0.01) and PSQI (r = 0.59, p < 0.001) scores. CONCLUSIONS: Subjective poor sleep and daytime sleepiness were associated with depressive symptoms in DLB. Given the cross-sectional nature of the present study, the directionality of this relationship cannot be determined, although this association did not appear to be mediated by sleep quality or daytime sleepiness. Nevertheless, these findings have clinical relevance; daytime sleepiness or poor sleep quality might indicate depression in DLB, and subsequent work should examine whether the treatment of depression can reduce excessive daytime sleepiness and improve sleep quality in DLB patients. Alternatively, more rigorous screening for sleep problems in DLB might assist the treatment of depression. © 2015 The Authors. International Journal of Geriatric Psychiatry published by John Wiley & Sons, Ltd.

Primary sleep disorder prevalence in patients with newly diagnosed Parkinson's disease.

BACKGROUND: Sleep disturbance occurs in up to 96% of patients with established Parkinson's disease (PD). We aimed to assess the prevalence of sleep disturbance in newly diagnosed PD. METHODS: Newly diagnosed PD patients and controls were recruited. Patients had motor, non-motor, and sleep assessments, including sleep questionnaires, respiratory home monitoring, actigraphy, and sleep diaries. Controls completed cognitive assessments, sleep questionnaires, and diaries. RESULTS: A total of 106 patients and 99 controls participated. Sleep questionnaire scores were no different between patients and controls. Daytime naps were increased in PD patients on sleep diaries (P > 0.003). Sleepiness was not associated with any motor or non-motor symptom. Periodic limb movements were increased but not associated with restless legs. CONCLUSIONS: Newly diagnosed PD patients had minimal differences in subjective or objective sleep disturbance compared to controls apart from increased daytime naps and symptoms such as dream-enacting behaviors of punching or grabbing. This contrasts with the literature assessing sleep in those with established PD.

Assessment of sleep and circadian rhythm disorders in the very old: the Newcastle 85+ Cohort Study.

OBJECTIVES: to examine the association between subjective and objective measures of sleep and wake and other health parameters in a cohort of the very old. DESIGN: a population-based cohort study. SETTING: primary care, North East England. PARTICIPANTS: four hundred and twenty-one men and women, aged 87-89, recruited to the Newcastle 85+ Study cohort. METHODS: sleep questionnaires were administered and sleep-wake patterns were assessed over 5-7 days with a novel wrist triaxial accelerometer. Associations between sleep measures and various health parameters, including mortality at 24 months, were examined. RESULTS: only 16% of participants perceived their sleep as severely disturbed as assessed with questionnaire responses. Wrist accelerometry showed marked variation between normal and abnormal sleep-wake cycles that did not correlate with the participants' perception of sleep. Impaired sleep-wake cycles were significantly associated with cognitive impairment, disability, depression, increased falls, body mass index and arthritis but not with any other specific disease markers and with decreased survival. CONCLUSIONS: commonly used sleep questionnaires do not differentiate well between those with objectively determined disturbance of sleep-wake cycles and those with normal cycles. Abnormal sleep-wake patterns are associated with institutionalisation, cognitive impairment, disability, depression and arthritis but not with other diseases; there is also an association with reduced survival.

Cortisol awakening response and spatial working memory in man: a U-shaped relationship.

OBJECTIVE: The association between hypothalamic-pituitary-adrenal (HPA)-axis function and cognition has long been investigated. An inverted U-shaped relationship has been described between various measures of HPA-axis function and neuropsychological performance in animals and man. Work with glucocorticoid receptor manipulation has corroborated these findings, with particular effects observed in relation to spatial working memory (SWM). As HPA-axis dysfunction is frequently found in patients with psychiatric illness, research in this area has potential implications for the treatment of the commonly observed cognitive impairment in such disorders. Here, we present the results of a pilot study examining the relationship between cortisol awakening response (CAR) and cognitive functions known to be susceptible to HPA-axis manipulation. METHODS: Nineteen healthy male volunteers were recruited, and their CAR and performance in a task of SWM were assessed. RESULTS: A highly significant quadratic relationship was observed between the CAR and SWM error rate (R(2)=0.63, p=0.001). CONCLUSION: We provide novel evidence supporting the existence of an inverted U-shaped relationship between corticosteroid levels and cognitive function in humans.

Development and evaluation of a personalised sleep care plan on child and adolescent in-patient mental health wards.

AIMS AND METHOD: The study evaluated a package of measures to improve sleep on psychiatric wards admitting patients from children and young people's services (CYPS). Sleep disturbance has significant impact on adolescent mental health, and in-patient wards can directly cause sleep disturbance, independent of the problem that led to admission. We developed a CYPS-specific package (TeenSleepWell) that promoted a better sleep environment, enhanced staff education about sleep, screened for sleep disorders, and raised awareness of benefits and side-effects of hypnotics. This included personalised sleep care plans that allowed a protected 8 h sleep period when safe. RESULTS: Evaluation over 2 years showed enhanced in-patient care: 57% of patients were able to have a protected sleep period. There was no increase in adverse events and there was a decrease in hypnotics issued. CLINICAL IMPLICATIONS: Improving sleep during in-patient CYPS admissions is possible and personalised sleep care plan should be a care standard.

Cerebellum and basal ganglia connectivity in isolated REM sleep behaviour disorder and Parkinson's disease: an exploratory study.

REM sleep behaviour disorder (RBD) is a parasomnia characterised by dream-enacting behaviour with loss of muscle atonia during REM sleep and is a prodromal feature of α-synucleinopathies like Parkinson's disease, dementia with Lewy bodies, and multiple system atrophy. Although cortical-to-subcortical connectivity is well-studied in RBD, cerebellar and subcortical nuclei reciprocal connectivity is less established. Nonetheless, it could be relevant since RBD pathology involves brainstem structures with an ascending gradient. In this study, we utilised resting-state functional MRI to investigate 13 people with isolated RBD (iRBD), 17 with Parkinson's disease and 16 healthy controls. We investigated the connectivity between the basal ganglia, thalamus and regions of the cerebellum. The cerebellum was segmented using a functional atlas, defined by a resting-state network-based parcellation, rather than an anatomical one. Controlling for age, we found a significant group difference (F4,82 = 5.47, pFDR = 0.017) in cerebellar-thalamic connectivity, with iRBD significantly lower compared to both control and Parkinson's disease. Specifically, cerebellar areas involved in this connectivity reduction were related to the default mode, language and fronto-parietal resting-state networks. Our findings show functional connectivity abnormalities in subcortical structures that are specific to iRBD and may be relevant from a pathophysiological standpoint. Further studies are needed to investigate how connectivity changes progress over time and whether specific changes predict disease course or phenoconversion.

Hypothalamic involvement in multiple system atrophy: A structural MRI study.

OBJECTIVE: To investigate hypothalamic atrophy and its clinical correlates in multiple system atrophy (MSA) in-vivo. BACKGROUND: MSA is characterized by autonomic dysfunction and parkinsonian/cerebellar manifestations. The hypothalamus regulates autonomic and homeostatic functions and is also involved in memory and learning processes. METHODS: 11 MSA, 18 Parkinson's Disease (PD) and 18 Healthy Controls (HC) were included in this study. A validated and automated hypothalamic segmentation tool was applied to 3D-T1-weighted images acquired on a 3T MRI scanner. MSA hypothalamic volumes were compared to those of PD and HC. Furthermore, the association between hypothalamic volumes and scores of autonomic, depressive, sleep and cognitive manifestations were investigated. RESULTS: Posterior hypothalamus volume was reduced in MSA compared to controls (t = 2.105, p = 0.041) and PD (t = 2.055, p = 0.046). Total hypothalamus showed a trend towards a reduction in MSA vs controls (t = 1.676, p = 0.101). Reduced posterior hypothalamus volume correlated with worse MoCA scores in the parkinsonian (MSA + PD) group and in each group separately, but not with autonomic, sleep, or depression scores. CONCLUSIONS: In-vivo structural hypothalamic involvement may be present in MSA. Reduced posterior hypothalamus volume, which includes the mammillary bodies and lateral hypothalamus, is associated with worse cognitive functioning. Larger studies on hypothalamic involvement in MSA and its clinical correlates are needed.

Pathogenic mitochondrial tRNA point mutations: nine novel mutations affirm their importance as a cause of mitochondrial disease.

Mutations in the mitochondrial genome, and in particular the mt-tRNAs, are an important cause of human disease. Accurate classification of the pathogenicity of novel variants is vital to allow accurate genetic counseling for patients and their families. The use of weighted criteria based on functional studies-outlined in a validated pathogenicity scoring system--is therefore invaluable in determining whether novel or rare mt-tRNA variants are pathogenic. Here, we describe the identification of nine novel mt--tRNA variants in nine families, in which the probands presented with a diverse range of clinical phenotypes including mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes, isolated progressive external ophthalmoplegia, epilepsy, deafness and diabetes. Each of the variants identified (m.4289T>C, MT-TI; m.5541C>T, MT-TW; m.5690A>G, MT-TN; m.7451A>T, MT-TS1; m.7554G>A, MT-TD; m.8304G>A, MT-TK; m.12206C>T, MT-TH; m.12317T>C, MT-TL2; m.16023G>A, MT-TP) was present in a different tRNA, with evidence in support of pathogenicity, and where possible, details of mutation transmission documented. Through the application of the pathogenicity scoring system, we have classified six of these variants as "definitely pathogenic" mutations (m.5541C>T, m.5690A>G, m.7451A>T, m.12206C>T, m.12317T>C, and m.16023G>A), whereas the remaining three currently lack sufficient evidence and are therefore classed as 'possibly pathogenic' (m.4289T>C, m.7554G>A, and m.8304G>A).

Restless leg syndrome is a treatable cause of sleep disturbance and fatigue in primary biliary cirrhosis.

BACKGROUND: Primary biliary cirrhosis (PBC) patients frequently describe sleep problems. The cause remains unclear and treatment is challenging. Restless leg syndrome (RLS) is a common sleep disorder. In this study, we systematically screened PBC patients for the presence of RLS. METHODS: Participants were recruited from our specialist PBC clinical service. Subjects completed the International Restless Leg Syndrome Study Group rating scale (IRLSS) a validated measure of the presence of RLS and its severity. Those fulfilling diagnostic criteria for RLS underwent foot actigraphy (CamNtech Actiwatch) to objectively assess periodic limb movement index (PLMI) (normal <5/h). RESULTS: Restless leg syndrome was assessed in 42 consecutive early stage PBC patients. Twelve (29%) fulfilled the IRLSS criteria for RLS. Scores were significantly higher in PBC compared to controls (P = 0.005). Twenty-four patients were further assessed with foot actigraphy for 3 nights (12 with subjective RLS symptoms and 12 with no RLS symptoms). Thirteen of twenty-four subjects had PLMI >5/h and four had moderate or severe PLMI >15/h. All moderate or severe PLMI subjects had subjective symptoms of moderate or severe RLS. No patients had PLMI >10 in the absence of RLS symptoms. Eleven PBC patients with symptomatic RLS went on to have treatment. Sixty-three per cent had clear benefit in restless leg symptoms and associated symptoms of fatigue. CONCLUSION: Restless leg syndrome symptoms are common and underdiagnosed in PBC patients. RLS represents a potential therapy for PBC patients with daytime sleepiness, fatigue and unpleasant lower limb symptoms and this is worthy of further studies in larger cohorts.

Novel assessment of microvascular changes in idiopathic restless legs syndrome (Willis-Ekbom disease).

Many patients with restless legs syndrome (Willis-Ekbom disease) complain of burning sensations in their feet associated with the desire to move, such that they seek cooler environments. This pilot study aimed to characterise the microvascular skin changes in 12 patients with restless legs syndrome compared with 12 age- and sex-matched controls. Patients with moderate or severe restless legs syndrome and controls underwent detailed thermovascular assessment in a controlled temperature room at three different stages (normothermic phase 23 °C, hot phase 30 °C, cold phase 18 °C). Microvascular activity was recorded during all phases by bilateral great toe laser-Doppler flowmetry and also by whole-body thermography. Patient and control measurements were compared. The study protocol was well tolerated. Parameters extracted from the laser-Doppler flowmetry measurements were used to model a logistic function using binary logistic regression. This demonstrated a statistically significant difference between patients with restless legs syndrome and healthy controls (P < 0.001). Visual inspection of the body thermography image sequences showed increased lower limb movement in patients with restless legs syndrome patients compared with controls. Thermography analysis also showed significant differences between foot temperatures in patients with restless legs syndrome compared with controls during the hot phase (P = 0.011). Notably, patients with restless legs syndrome had more uniform foot temperatures, whereas controls had a wider variability in surface temperature across the feet. This novel study demonstrates impaired microvascular circulation in patients with restless legs syndrome in comparison to matched controls and a potential mechanism for the sensation of burning feet. The protocol also provides an experimental paradigm to test therapeutic interventions for the future.

Corrigendum: The longitudinal progression of autonomic dysfunction in Parkinson's disease: a 7-year study.

[This corrects the article DOI: 10.3389/fneur.2023.1155669.].

The longitudinal progression of autonomic dysfunction in Parkinson's disease: A 7-year study.

Background: Autonomic dysfunction, including gastrointestinal, cardiovascular, and urinary dysfunction, is often present in early Parkinson's Disease (PD). However, the knowledge of the longitudinal progression of these symptoms, and the connection between different autonomic domains, is limited. Furthermore, the relationship between the presence of autonomic symptoms in early-stage PD and olfactory dysfunction, a possible marker of central nervous system involvement, has not been fully investigated. Objectives: We aimed to investigate the occurrence and progression of autonomic dysfunction in recently diagnosed (< 2 years) untreated PD patients and determine any coexistence of symptoms in individual patients. We also investigated the relationship between autonomic symptoms, olfactory dysfunction, and motor impairment. Methods: Data were obtained from the Parkinson's Progression Markers Initiative (PPMI) database. Autonomic dysfunction was measured using the Scales for Outcomes in Parkinson's Disease (SCOPA-AUT). Symptom frequency and mean scores over 7 years were determined. The simultaneous occurrence of different autonomic symptoms was also examined. Finally, the relationships between SCOPA-AUT scores, olfactory dysfunction, and motor impairment were investigated using the University of Pennsylvania Smell Identification Test (UPSIT) and the Movement Disorder Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS), respectively. Results: Follow-up data were available for 7 years for 171 PD patients and for 5 years for 136 HCs. Mean SCOPA-AUT score increased significantly from baseline to the 7-year follow-up for each autonomic domain, except for female sexual dysfunction. Most patients reported three or more autonomic symptoms. Common clusters of symptoms were composed of combinations of gastrointestinal, urinary, thermoregulatory, and sexual dysfunction. At baseline, greater SCOPA-AUT total score was associated with lower UPSIT scores (r = -0.209, p = 0.006) and with greater total MDS-UDPRS III score (r = 0.218, p = 0.004). Conclusions: Autonomic dysfunction, often with coexistence of autonomic manifestations, is common in early PD and progressively worsens over the first 7 years of disease, suggesting that these symptoms should be addressed with appropriate treatments early in the disease. The association between greater autonomic dysfunction and greater olfactory impairment, coupled with the association with more severe motor scores at baseline, indicates that patients who show more severe autonomic dysfunction could also have more severe involvement of the central nervous system at the time of diagnosis.