Diane Swallow

Vascular disease and vascular risk factors in relation to motor features and cognition in early Parkinson's disease

The purpose of this study was to examine the relationship between vascular disease (and vascular risk factors), cognition and motor phenotype in Parkinsons disease (PD).

Equating scores of the University of Pennsylvania Smell Identification Test and Sniffin' Sticks test in patients with Parkinson's disease

Background Impaired olfaction is an important feature in Parkinsons disease (PD) and other neurological diseases. A variety of smell identification tests exist such as “Sniffin’ Sticks” and the University of Pennsylvania Smell Identification Test (UPSIT). An important part of research is being able to replicate findings or combining studies in a meta-analysis. This is difficult if olfaction has been measured using different metrics. We present conversion methods between the: UPSIT, Sniffin’ 16, and Brief-SIT (B-SIT); and Sniffin’ 12 and Sniffin’ 16 odour identification tests. Methods We used two incident cohorts of patients with PD who were tested with either the Sniffin’ 16 (n = 1131) or UPSIT (n = 980) and a validation dataset of 128 individuals who took both tests. We used the equipercentile and Item Response Theory (IRT) methods to equate the olfaction scales. Results The equipercentile conversion suggested some bias between UPSIT and Sniffin’ 16 tests across the two groups. The IRT method shows very good characteristics between the true and converted Sniffin’ 16 (delta mean = 0.14, median = 0) based on UPSIT. The equipercentile conversion between the Sniffin’ 12 and 16 item worked well (delta mean = 0.01, median = 0). The UPSIT to B-SIT conversion showed evidence of bias but amongst PD cases worked well (mean delta = −0.08, median = 0). Conclusion We have demonstrated that one can convert UPSIT to B-SIT or Sniffin’ 16, and Sniffin’ 12 to 16 scores in a valid way. This can facilitate direct comparison between tests aiding future collaborative analyses and evidence synthesis.

Tracking Parkinson's: Study Design and Baseline Patient Data.

Background: There is wide variation in the phenotypic expression of Parkinson’s disease (PD), which is driven by both genetic and epidemiological influences. Objectives: To define and explain variation in the clinical phenotype of PD, in relation to genotypic variation. Methods: Tracking Parkinson’s is a multicentre prospective longitudinal epidemiologic and biomarker study of PD. Patients attending specialist clinics in the United Kingdom with recent onset (<3.5 years) and young onset (diagnosed <50 years of age) PD were enrolled. Motor, non-motor and quality of life assessments were performed using validated scales. Cases are followed up 6 monthly up to 4.5 years for recent onset PD, and up to 1 year for young onset PD. We present here baseline clinical data from this large and demographically representative cohort. Results: 2247 PD cases were recruited (1987 recent onset, 260 young onset). Recent onset cases had a mean (standard deviation, SD) age of 67.6 years (9.3) at study entry, 65.7% males, with disease duration 1.3 years (0.9), MDS-UPDRS 3 scores 22.9 (12.3), LEDD 295 mg/day (211) and PDQ-8 score 5.9 (4.8). Young onset cases were 53.5 years old (7.8) at study entry, 66.9% male, with disease duration 10.2 years (6.7), MDS-UPDRS 3 scores 27.4 (15.3), LEDD 926 mg/day (567) and PDQ-8 score 11.6 (6.1). Conclusions: We have established a large clinical PD cohort, consisting of young onset and recent onset cases, which is designed to evaluate variation in clinical expression, in relation to genetic influences, and which offers a platform for future imaging and biomarker research.

Olfaction in Parkin single and compound heterozygotes in a cohort of young onset Parkinson's disease patients.

Parkin related Parkinsons disease (PD) is differentiated from idiopathic PD by absent or sparse Lewy bodies, and preserved olfaction. The significance of single Parkin mutations in the pathogenesis of PD is debated.

Repeatability of cerebrospinal fluid constant rate infusion study

Infusion tests are important tools to assess cerebrospinal fluid (CSF)dynamics used in the preoperative selection of patients for shunt surgery, or to predict the scope of improvement from shunt revision. The aim of this study was to assess the repeatability of the key quantitative parameters describing CSF dynamics that are determined with infusion testing.

Variation in Recent Onset Parkinson's Disease: Implications for Prodromal Detection.

Background: The detection of prodromal Parkinson’s disease (PD) is desirable to test drugs with neuroprotective potential, but will be affected by known disease variations. Objective: To assess the prevalence of four key non-motor prodromal PD markers, and evaluate the sensitivity of case detection when non-motor screening tools for prodromal PD are implemented in an early clinical PD cohort. Methods: Hyposmia (University of Pennsylvania smell identification test ≤15th centile or Sniffin’ Sticks at or ≤10th centile corrected for age and sex), rapid-eye movement sleep behaviour disorder (RBD questionnaire >4), constipation (<1 daily spontaneous bowel motion) and depression (Leeds >6) were recorded in recent onset PD cases, and proposed non-motor screening criteria applied. Results: In 1,719 PD cases, mean age 68.6 years (SD 8.1), 65.5% male, mean disease duration 1.3 years (SD 0.9), 72.2% were hyposmic, 43.3% had RBD, 22.1% depression, and 21.5% constipation. 11.6% of cases had no key non-motor features, 38.8% one, 32.1% two, 15.5% three, and 2.0% all four. Increasing numbers of non-motor features were associated with younger age (p = 0.019), higher motor scores (p < 0.001), more postural instability gait difficulty (PIGD) (p < 0.001), greater cognitive impairment (p < 0.001) and higher total non-motor burden (p < 0.001). Cases with hyposmia alone were younger (p < 0.001), had less severe cognitive (p = 0.006) and other non-motor features (p < 0.001). All screening criteria selected younger patients (p = 0.001, p < 0.001), three of four greater overall non-motor burden (p = 0.005, p < 0.001), and inclusion of RBD more cognitive impairment (p = 0.003, p = 0.001) and PIGD (p = 0.004, p = 0.001). Conclusions: Varying sensitivity levels, and age and phenotype selectivity, are found when different non-motor screening methods to detect prodromal PD are applied to an early clinical PD cohort.

Statins are underused in recent-onset Parkinson's disease with increased vascular risk: findings from the UK Tracking Parkinson's and Oxford Parkinson's Disease Centre (OPDC) discovery cohorts

Background Cardiovascular disease (CVD) influences phenotypic variation in Parkinsons disease (PD), and is usually an indication for statin therapy. It is less clear whether cardiovascular risk factors influence PD phenotype, and if statins are prescribed appropriately. Objectives To quantify vascular risk and statin use in recent-onset PD, and examine the relationship between vascular risk, PD severity and phenotype. Methods Cardiovascular risk was quantified using the QRISK2 calculator (high ≥20%, medium ≥10 and <20%, low risk <10%). Motor severity and phenotype were assessed using the Movement Disorder Society Unified PD Rating Scale (UPDRS) and cognition by the Montreal cognitive assessment. Results In 2909 individuals with recent-onset PD, the mean age was 67.5 years (SD 9.3), 63.5% were men and the mean disease duration was 1.3 years (SD 0.9). 33.8% of cases had high vascular risk, 28.7% medium risk, and 22.3% low risk, while 15.2% of cases had established CVD. Increasing vascular risk and CVD were associated with older age (p<0.001), worse motor score (p<0.001), more cognitive impairment (p<0.001) and worse motor phenotype (p=0.021). Statins were prescribed in 37.2% with high vascular risk, 15.1% with medium vascular risk and 6.5% with low vascular risk, which compared with statin usage in 75.3% of those with CVD. Conclusions Over 60% of recent-onset PD patients have high or medium cardiovascular risk (meriting statin usage), which is associated with a worse motor and cognitive phenotype. Statins are underused in these patients, compared with those with vascular disease, which is a missed opportunity for preventive treatment. Trial registration number GN11NE062, NCT02881099.

Evaluation of a protocol-based treatment strategy for postoperative diabetes insipidus in craniopharyngioma.

BACKGROUND Postoperative diabetes insipidus (DI) is a significant cause of morbidity in craniopharyngiomas (CP) and its effective management improves outcome. OBJECTIVE The objective was to determine the efficacy of a treatment protocol in the management of early postoperative DI in CP. MATERIALS AND METHODS The quality of postoperative DI control in a prospective cohort of 26 patients treated utilizing a strict protocol (Group 1) was compared with a retrospective cohort of 34 patients (Group 2) managed without a protocol. A 6-h urine output more than 4 ml/kg/h or serum sodium (Na+) more than 145 mEq/L was diagnosed as DI. The quality of DI control was assessed by determining the incidence of serum Na+ values above 150 mEq/L or below 130 mEq/L and the incidence of wide (>10 mEq/L) intra-day fluctuations of serum Na+ levels. RESULTS The occurrence of high and low serum Na+ levels was significantly lower in Group 1(P = 0.032). The incidence of serum Na+ exceeding 150 mEq/L on postoperative days 2 and 3 was significantly higher in Group 2 as compared with those in Group 1 (25% vs. 7.6%, P = 0.0008). Hyponatremia was more frequent in Group 2 and tended to occur on postoperative days 6, 7, and 8 (14.2% vs. 3.2%; P = 0.004). The same patients who had hypernatremia in the early part of the week later developed hyponatremia. Although the incidence of wide intra-day fluctuations (>10 mEq/L) was higher in Group 2, it did not reach statistical significance. CONCLUSION A strict protocol based management results in better control of postoperative DI in CP.

Developing and validating Parkinson’s disease subtypes and their motor and cognitive progression

Objectives To use a data-driven approach to determine the existence and natural history of subtypes of Parkinson’s disease (PD) using two large independent cohorts of patients newly diagnosed with this condition. Methods 1601 and 944 patients with idiopathic PD, from Tracking Parkinson’s and Discovery cohorts, respectively, were evaluated in motor, cognitive and non-motor domains at the baseline assessment. Patients were recently diagnosed at entry (within 3.5 years of diagnosis) and were followed up every 18 months. We used a factor analysis followed by a k-means cluster analysis, while prognosis was measured using random slope and intercept models. Results We identified four clusters: (1)  fast motor progression with symmetrical motor disease, poor olfaction, cognition and postural hypotension; (2) mild motor and non-motor disease with intermediate motor progression; (3) severe motor disease, poor psychological well-being and  poor sleep with an intermediate motor progression; (4) slow motor progression with tremor-dominant, unilateral disease. Clusters were moderately to substantially stable across the two cohorts (kappa 0.58). Cluster 1 had the fastest motor progression in Tracking Parkinson’s at 3.2 (95% CI 2.8 to 3.6) UPDRS III points per year while cluster 4 had the slowest at 0.6 (0.1–1.1). In Tracking Parkinson’s, cluster 2 had the largest response to levodopa 36.3% and cluster 4 the lowest 28.8%. Conclusions We have found four novel clusters that replicated well across two independent early PD cohorts and were associated with levodopa response and motor progression rates. This has potential implications for better understanding disease pathophysiology and the relevance of patient stratification in future clinical trials.

Nonmotor symptoms in patients without evidence of dopaminergic deficit

We read with interest the recent paper by Sprenger and colleagues, noting particularly their conclusions regarding the higher overall frequency of nonmotor symptoms (when compared with controls) in cases diagnosed clinically as PD, but in whom subsequent dopamine transporter functional neuroimaging was normal. We also note the higher frequency of selected nonmotor features (orthostatic hypotension, cardiovascular and thermoregulatory dysfunction) when comparing the cases with SWEDDs to cases with PD. In addition to several proposed reasons for these observations, we would like to offer an additional explanation based on the clinical diagnostic process. It appears likely that the clinician is swayed toward a diagnosis of PD in SWEDD cases when such nonmotor features are prominent or severe. This would be more likely when motor features are less complete or less severe, noting that the features required for inclusion in the Parkinson’s Progression Markers Initiative (PPMI) study could be a single entity (asymmetric resting tremor or asymmetric bradykinesia) or dual features without bradykinesia (at least 2 of the following: resting tremor, bradykinesia, rigidity; must have either resting tremor or bradykinesia). In support of this, the motor component of the UPDRS score is generally lower in SWEDDs than in PD cases despite the higher UPDRS part 1 scores in SWEDDs. In addition, the overall lower scores for total UPDRS in SWEDDs but not in PD in the PPMI study is also noted. The current research focus on these nonmotor features will provide supporting evidence for their potential inclusion into diagnostic criteria for PD. However, the lack of specificity for several of these features has become evident as methods to screen for premotor PD are explored. Emphasis on a set of nonmotor features and/or the presence of a high nonmotor burden as diagnostic support for PD in patients presenting to movement disorder clinics could therefore contribute to misdiagnosis, particularly when fulfillment of the classic motor diagnostic criteria is less definite.