PREDICT-PD: An online approach to prospectively identify risk indicators of Parkinson's disease.

BACKGROUND: A number of early features can precede the diagnosis of Parkinson's disease (PD). OBJECTIVE: To test an online, evidence-based algorithm to identify risk indicators of PD in the UK population. METHODS: Participants aged 60 to 80 years without PD completed an online survey and keyboard-tapping task annually over 3 years, and underwent smell tests and genotyping for glucocerebrosidase (GBA) and leucine-rich repeat kinase 2 (LRRK2) mutations. Risk scores were calculated based on the results of a systematic review of risk factors and early features of PD, and individuals were grouped into higher (above 15th centile), medium, and lower risk groups (below 85th centile). Previously defined indicators of increased risk of PD ("intermediate markers"), including smell loss, rapid eye movement-sleep behavior disorder, and finger-tapping speed, and incident PD were used as outcomes. The correlation of risk scores with intermediate markers and movement of individuals between risk groups was assessed each year and prospectively. Exploratory Cox regression analyses with incident PD as the dependent variable were performed. RESULTS: A total of 1323 participants were recruited at baseline and >79% completed assessments each year. Annual risk scores were correlated with intermediate markers of PD each year and baseline scores were correlated with intermediate markers during follow-up (all P values < 0.001). Incident PD diagnoses during follow-up were significantly associated with baseline risk score (hazard ratio = 4.39, P = .045). GBA variants or G2019S LRRK2 mutations were found in 47 participants, and the predictive power for incident PD was improved by the addition of genetic variants to risk scores. CONCLUSIONS: The online PREDICT-PD algorithm is a unique and simple method to identify indicators of PD risk. © 2017 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.

PREDICT-PD: identifying risk of Parkinson's disease in the community: methods and baseline results.

OBJECTIVES: To present methods and baseline results for an online screening tool to identify increased risk for Parkinson's disease (PD) in the UK population. METHODS: Risk estimates for future PD were derived from the results of a systematic review of risk factors and early features of PD. Participants aged 60-80 years without PD were recruited by self-referral. They completed an online survey (including family history, non-motor symptoms and lifestyle factors), a keyboard-tapping task and the University of Pennsylvania Smell Identification Test. Risk scores were calculated based on survey answers. Preliminary support for the validity of this algorithm was assessed by comparing those estimated to be higher risk for PD with those at lower risk using proxies, including smell loss, REM-sleep behaviour disorder and reduced tapping speed, and by assessing associations in the whole group. RESULTS: 1324 eligible participants completed the survey and 1146 undertook the keyboard-tapping task. Smell tests were sent to 1065 participants. Comparing the 100 highest-risk participants and 100 lowest-risk participants, median University of Pennsylvania Smell Identification Test scores were 30/40 versus 33/40 (p<0.001), mean number of key taps in 30 s were 55 versus 58 (p=0.045), and 24% versus 10% scored above cut-off for REM-sleep behaviour disorder (p=0.008). Regression analyses showed increasing risk scores were associated with worse scores in the three proxies across the whole group (p≤0.001). CONCLUSIONS: PREDICT-PD is the first study to systematically combine risk factors for PD in the general population. Validity to predict risk of PD will be tested through longitudinal follow-up of incident PD diagnosis.

The forearm elevation-compression test: a novel test for carpal tunnel syndrome.

BACKGROUND: As the time available to spend with patients decreases, a rapid test for bedside diagnosis of carpal tunnel syndrome (CTS) could be useful. AIM: We describe the forearm elevation-compression test (FECT) in this context. The FECT was assessed in 40 patients with clinically suspected carpal tunnel syndrome and compared to Tinel's and Phalen's signs. Routine electromyography and nerve conduction tests (EMG/NCT) were performed in all cases. In addition, 85 healthy controls were examined by FECT and compared to the patient group. RESULTS: All three provocative tests, particularly FECT were frequently positive in suspected CTS. Neurophysiological tests were normal in 5 of 40 cases of clinically suspected CTS and the FECT was positive in all of these suggesting a positive predictive value of 87.5% if one accepts EMG/NCT as the reference. Amongst the healthy controls 18 of 85 (21.2%) were positive on the FECT suggestive of a high false positive rate or subclinical disease. CONCLUSION: It is proposed that the FECT is a useful addition to the clinical examination of suspected CTS. Although the positive rate may be falsely elevated this is offset by restricting the latency for tingling onset to 10 seconds or less (FECT2).

Meta-analysis of early nonmotor features and risk factors for Parkinson disease.

OBJECTIVE: To evaluate the association between diagnosis of Parkinson disease (PD) and risk factors or early symptoms amenable to population-based screening. METHODS: A systematic review and meta-analysis of risk factors for PD. RESULTS: The strongest associations with later diagnosis of PD were found for having a first-degree or any relative with PD (odds ratio [OR], 3.23; 95% confidence interval [CI], 2.65-3.93 and OR, 4.45; 95% CI, 3.39-5.83) or any relative with tremor (OR, 2.74; 95% CI, 2.10-3.57), constipation (relative risk [RR], 2.34; 95% CI, 1.55-3.53), or lack of smoking history (current vs never: RR, 0.44; 95% CI, 0.39-0.50), each at least doubling the risk of PD. Further positive significant associations were found for history of anxiety or depression, pesticide exposure, head injury, rural living, beta-blockers, farming occupation, and well-water drinking, and negative significant associations were found for coffee drinking, hypertension, nonsteroidal anti-inflammatory drugs, calcium channel blockers, and alcohol, but not for diabetes mellitus, cancer, oral contraceptive pill use, surgical menopause, hormone replacement therapy, statins, acetaminophen/paracetamol, aspirin, tea drinking, history of general anesthesia, or gastric ulcers. In the systematic review, additional associations included negative associations with raised serum urate, and single studies or studies with conflicting results. INTERPRETATION: The strongest risk factors associated with later PD diagnosis are having a family history of PD or tremor, a history of constipation, and lack of smoking history. Further factors also but less strongly contribute to risk of PD diagnosis or, as some premotor symptoms, require further standardized studies to demonstrate the magnitude of risk associated with them.

Myopia in late adolescence and subsequent multiple sclerosis among men.

BACKGROUND: Risk factors such as low vitamin D level has been implicated in the etiology of multiple sclerosis (MS) and may be relevant to myopia, such that there may be an association between myopia and MS. METHODS: Using linked Swedish national register data, we conducted a cohort study of men who were born in Sweden between 1950 and 1992, lived in Sweden between 1990 and 2018, and enrolled in military conscription assessment (n = 1,847,754). Myopia was defined based on the spherical equivalent refraction measured at conscription assessment, around age 18 years. Multiple sclerosis was identified using the Patient Register. Cox regression produced hazard ratios (HR) with 95% confidence intervals (95% CI), with adjustment for demographic and childhood socioeconomic characteristics and residential region. Due to changes in the assessment of refractive error, the analysis was stratified into two groups by the year of conscription assessment: 1969-1997 and 1997-2010. RESULTS: Among 1,559,859 individuals during a maximum of 48 years of follow-up from age 20 to 68 years (44,715,603 person-years), there were 3,134 MS events, and the incidence rate 7.0 (95% CI [6.8, 7.3] per 100,000 person-years). Among individuals with conscription assessments during 1997-2010, there were 380 MS events. There was no evidence of an association between myopia and MS, with HR 1.09 (95% CI 0.83, 1.43). Among individuals who underwent conscription assessment in 1969-1997, there were 2754 MS events. After adjusting for all covariates, there was no evidence of an association between myopia and MS (HR 0.99 [95% CI 0.91, 1.09]). CONCLUSION: Myopia in late adolescence is not associated with a subsequent raised risk of MS and thus there does not appear to be important shared risk factors.

CNS resilience in the progression of MS.

Resilience; Progressive multiple sclerosis; Genomics.

Is it ethical to use teriflunomide as an active comparator in phase 3 trials?

Ethical concerns have been raised about the practice of using teriflunomide, an oral licensed disease-modifying therapy, as an active comparator in phase 3 multiple sclerosis (MS) trials. The assumption is based on the perceived low efficacy of teriflunomide as judged by its effect on relapses and focal MRI activity. However, when you look beyond focal inflammation, teriflunomide has a robust impact on disability progression and a similar effect to the anti-CD20 monoclonal antibody therapies on slowing down the accelerated brain volume loss associated with MS. Teriflunomide is also more effective when used second or third line. The other classes of disease-modifying therapies have problems with their use as active comparators in clinical trials. Using a non-inferiority or equivalence trial design has its own unique set of regulatory and ethical challenges and is not necessarily a solution. There are also economic, altruistic and pragmatic reasons for continuing to use teriflunomide as an active comparator in MS clinical trials. An online survey indicates that the majority of the MS community feels it is still ethical to randomise subjects to teriflunomide and that procedures can be put in place to protect trial subjects randomised to teriflunomide. Therefore, we still have equipoise, and teriflunomide comparator trials are ethical.

Identifying prodromal Parkinson's disease: pre-motor disorders in Parkinson's disease.

Increasing recognition that Parkinson's disease (PD) may start outside of the substantia nigra has led to a rapidly expanding effort to define prodromal stages of PD, before motor signs permit classical diagnosis. Many of these efforts center around the identification of clinical non-motor symptoms and signs of disease. There is now direct evidence that olfaction, rapid eye movement (REM) sleep behavior disorder (RBD), constipation, and depression can be present in prodromal PD. In addition, there is suggestive evidence that visual changes, other autonomic symptoms, and subtle cognitive changes may also be present at prodromal stages. A critical issue in utility of these prodromal markers will be assessment of sensitivity, specificity, and positive and negative predictive values. Although these have yet to be fully defined, olfactory deficits, some visual changes, and autonomic symptoms occur in the majority of PD patients at diagnosis, suggesting good potential sensitivity. However, with the exception of RBD and perhaps some specific autonomic measures, specificity, and positive predictive value of these markers may be insufficient to be used alone as identifiers of prodromal disease. The evidence for the utility of olfaction, RBD, autonomic markers, visual changes, mood disorders, and cognitive loss as markers of prodromal PD and the potential sensitivity and specificity of these markers are summarized.

Smell, taste and COVID-19: testing is essential.

During the COVID-19 pandemic, it became clear that smell and taste (chemosensory) disturbance is very common in the early stages of disease. This article addresses (i) why COVID-19 specifically targets the modalities of smell and possibly taste and what is the mechanism, (ii) what is the frequency of smell and taste loss and (iii) what is the overall prognosis. It is suggested that mouth-breathers may be at particular risk of COVID-19. Symptom-based questionnaires are likely to under-estimate the prevalence of chemosensory impairment by as much as 50%. The prevalence of smell loss is so high that a person who has normal olfaction on formal testing is unlikely to be infected significantly with Cov-2. Furthermore, someone without symptoms who has an abnormal smell test could still be infected and liable to spread the disease. Brief, low-cost, olfactory tests are available that would permit a high throughput in field stations and airports. A normal result might obviate the need for a nasopharyngeal swab for the Cov-2 virus.

Lewy pathology in the submandibular gland of individuals with incidental Lewy body disease and sporadic Parkinson's disease.

A retrospective autopsy-based study of the human submandibular gland, one of the three major salivary glands, together with anatomically related peripheral structures (cervical superior ganglion, cervical sympathetic trunk, vagal nerve at the level of the carotid bifurcation), was conducted on a cohort consisting of 33 individuals, including 9 patients with neuropathologically confirmed Parkinson's disease (PD), three individuals with incidental Lewy body disease (iLBD), 2 individuals with neuropathologically confirmed multiple system atrophy (MSA), and 19 controls, using alpha-synuclein immunohistochemistry in 100 mum polyethylene glycol-embedded tissue sections. Lewy pathology (LP) was present in the submandibular glands and cervical superior ganglia in PD (9/9 cases) and iLBD (2/3 cases) but not in MSA or controls. The cervical sympathetic trunk (7/9 PD cases, 2/3 iLBD cases) and peripheral vagal nerves (9/9 PD cases, 2/3 iLBD cases) also displayed LP. The results are discussed within the context of hyposmia as well as autonomic dysfunction in PD (sialorrhea, sialopenia, dysphagia). Potential disease-related changes in salivary volume, contents, and viscosity might make it possible, in combination with other tests, to employ human saliva as a biomarker.

The McDonald Criteria for Multiple Sclerosis: time for clarification.

The McDonald Criteria for Multiple Sclerosis in general have replaced the Poser criteria. Despite this, many consider that there are still areas of ambiguity. In this study, neurologists completed a questionnaire about familiarity with, usefulness and applicability of the McDonald Criteria for Multiple Sclerosis. Understanding of 'attack'; objective clinical evidence; 'two or more lesions' and their ability to interpret case scenarios was evaluated. Responses were analysed overall and by skill group. Ninety-seven consultants and 30 trainees responded, of whom 37 operated a multiple sclerosis clinic ('experts'). Some (62%) thought the McDonald Criteria for Multiple Sclerosis were useful, and 31% found them confusing or difficult to apply; 38% thought the criteria should be applied universally, others (14-28%) favoured their use for drug trials/research, and 17% rarely used them. Thirty-six (29.1%) thought the McDonald Criteria for Multiple Sclerosis specified two categories: 'MS and not MS', but others considered 'possible' or 'probable' multiple sclerosis were permitted. Experts understood better 'an attack' and 'objective clinical evidence'. All skill groups comprehended poorly what constituted an episode of demyelination, and whether Lhermitte's phenomenon was acceptable as evidence for cervical cord demyelination. A consistent response was given by 44-50% to 'two or more lesions', although this is not well defined. Criteria for primary progressive multiple sclerosis were understood well. We conclude that the McDonald Criteria for Multiple Sclerosis have improved diagnosis but areas of misinterpretation remain, particularly the definition of 'an attack', 'objective clinical evidence' and 'two or more lesions'. There was uncertainty about how many multiple sclerosis categories were permitted and whether the terms 'possible' and 'probable' were allowable. Further clarification might allow the criteria to be applied more consistently.

Multiple sclerosis, lymphoma and nasopharyngeal carcinoma: the central role of Epstein-Barr virus?

BACKGROUND: Multiple sclerosis (MS) and Hodgkin lymphoma (HL) share epidemiologic characteristics suggesting a possible common etiology. Epstein-Barr virus (EBV) is associated with HL, Burkitt lymphoma, some varieties of non-Hodgkin lymphoma (NHL) and nasopharyngeal carcinoma (NPC). METHOD: Patients were located through MS databases for (a) Barking and Havering, NE London; catchment approximately 400,000; MS patient number 751, and (b) Nottingham, catchment approximately 2,000,000; MS patient number 1,236. Search was undertaken for lymphoma or NPC and diagnosis of MS verified by McDonald criteria. RESULTS: We identified five UK-born and resident patients of interest: (1) male with onset HL aged 20 years developing relapsing-remitting MS 11 years later; (2) female with severe relapsing-remitting MS whose partner developed NHL, 5 years after MS diagnosis; (3) female with secondary progressive MS beginning at age 38 years who developed NHL 25 years later; (4) female diagnosed with MS aged 19 years who developed HL 4 years later, and (5) female with hereditary motor and sensory neuropathy developing cervical cancer at the age of 32 years, NPC at 33 years, and RR MS at 36 years. CONCLUSION: Our study supports a possible association between MS, HL, NHL, and perhaps NPC all of which are associated with EBV infection.

Abnormality of taste and smell in Parkinson's disease.

BACKGROUND: Smell sense is impaired in classic Parkinson's disease (PD). An initial study found no change in taste threshold in non-demented PD subjects and pathological studies suggest that the first relay for taste, the nucleus of the solitary tract, is spared. We wished to determine if taste is abnormal in PD and whether it is associated with smell dysfunction. METHODS: Taste threshold was estimated using the Rion electrogustometer and olfaction by the University of Pennsylvania Smell Identification Test (UPSIT) in 75 non-demented PD patients and 74 controls. RESULTS: There was a significant impairment of taste threshold and severe disorder of smell identification in the PD group. Age, duration of symptoms, disability, and smoking had no important effect on threshold measurement and there was no correlation between taste and smell dysfunction. Sensitivity analysis suggested that a provisional diagnosis of PD would be confirmed if smell or taste were abnormal; conversely, the diagnosis would merit review if both modalities were normal. CONCLUSIONS: Impaired taste appreciation was found in about 27% of patients with clinically defined PD. There were no important effects from age, disease severity or smell sense. Given the sparing of the first and second order taste neurones in PD, disorder of taste in PD most likely signifies involvement of the frontal operculum or orbitofrontal cortex, in keeping with advanced disease, although confounding by drug effects and changes in salivary constitution could not be excluded completely.

Chemosensory dysfunction in neurodegenerative diseases.

A number of neurodegenerative diseases are accompanied by disordered smell function. The degree of dysfunction can vary among different diseases, such that olfactory testing can aid in differentiating, for example, Alzheimer's disease (AD) from major affective disorder and Parkinson's disease (PD) from progressive supranuclear palsy. Unfortunately, altered smell function often goes unrecognized by patients and physicians alike until formal testing is undertaken. Such testing uniquely probes brain regions not commonly examined in physical examinations and can identify, in some cases, patients who are already in the "preclinical" stage of disease. Awareness of this fact is one reason why the Quality Standards Committee of the American Academy of Neurology has designated smell dysfunction as one of the key diagnostic criteria for PD. The same recommendation has been made by the Movement Disorder Society for both the diagnosis of PD and identification of prodromal PD. Similar suggestions are proposed to include olfactory dysfunction as an additional research criterion for the diagnosis of AD. Although taste impairment, i.e., altered sweet, sour, bitter, salty, and umami perception, has also been demonstrated in some disorders, taste has received much less scientific attention than smell. In this review, we assess what is known about the smell and taste disorders of a wide range of neurodegenerative diseases and describe studies seeking to understand their pathologic underpinnings.

Parkinson's disease and aging: same or different process?

Parkinson's disease (PD), which probably commences in the olfactory bulb and nuclei of IX and X, may represent accelerated normal aging or a disease specific process. The olfactory and motor disorders are associated in PD, so that smell loss should reflect the underlying disease course. Information on age-associated decline can be obtained by single measurement from cross-sectional analysis of patients and controls of different ages, because the observed between-subject picture may reflect a similar within-subject pattern. University of Pennsylvania Smell Identification Test (UPSIT) scores were examined for aging effects in 263 controls and 266 PD patients. Three models were applied that are (a) simple linear regression and (b) quadratic term in age: (i) assuming two parallel curves and (ii) allowing for two separate curves. Both groups declined with age. All three models were fitted successfully to the cross-sectional data and none suggested that the lower mean UPSIT score in patients compared to controls was a premature ageing effect. The mean PD-UPSIT score even at the age of 40, was lower than the control mean at the upper life-span limit, implied that the decline in olfaction in PD is faster than simple aging. Extrapolation back in time suggested onset before birth, which is unlikely and implies that at some point there is a more rapid decline than observed in this sample. On the basis of olfactory measurement, our data are consistent with the proposal that PD starts as an acute event, followed by further disease progression more rapid than simple aging.