Naveed Malek

Alpha-synuclein in peripheral tissues and body fluids as a biomarker for Parkinson's disease – a systematic review

Parkinsons disease (PD) is neuropathologically characterized as an alpha‐synucleinopathy. Alpha‐synuclein‐containing inclusions are stained as Lewy bodies and Lewy neurites in the brain, which are the pathological hallmark of PD. However, alpha‐synuclein‐containing inclusions in PD are not restricted to the central nervous system, but are also found in peripheral tissues. Alpha‐synuclein levels can also be measured in body fluids. The aim of this study was to conduct a systematic review of available evidence to determine the utility of alpha‐synuclein as a peripheral biomarker of PD. We searched PubMed (1948 to 26 May 2013), Embase (1974 to 26 May 2013), the Cochrane Library (up to 26 May 2013), LILACS (up to 26 May 2013) and CINAHL (up to 26 May 2013) for the studies of alpha‐synuclein in peripheral tissues or body fluids in PD. A total of 49 studies fulfilled the search criteria. Peripheral tissues such as colonic mucosa showed a sensitivity of 42–90% and a specificity of 100%; submandibular salivary glands showed sensitivity and specificity of 100%; skin biopsy showed 19% sensitivity and 80% specificity in detecting alpha‐synuclein pathology. CSF alpha‐synuclein had 71–94% sensitivity and 25–53% specificity for distinguishing PD from controls. Plasma alpha‐synuclein had 48–53% sensitivity and 69–85% specificity. Neither plasma nor CSF alpha‐synuclein is presently a reliable marker of PD. This differs from alpha‐synuclein in solid tissue samples of the enteric and autonomic nervous system, which offer some potential as a surrogate marker of brain synucleinopathy.

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).

Phase IIa randomized double‐blind, placebo‐controlled study of inhaled apomorphine as acute challenge for rescuing ‘off’ periods in patients with established Parkinson's disease

In this first study of inhaled apomorphine (VR040) in patients with Parkinsons disease, the primary objective was to find the minimum efficacious dose of apomorphine that was useful in rescuing patients during ‘off’ periods. Safety, tolerability and pharmacokinetics of inhaled apomorphine were assessed during the study.

Inhaled dry powder apomorphine (VR040) for ‘off ’ periods in Parkinson's disease: an in‐clinic double‐blind dose ranging study

‘Off’ periods increase as Parkinsons disease (PD) progresses and the benefits of standard therapy wane. Subcutaneous apomorphine rescues ‘off’ periods, but patient self‐injection and adverse cutaneous effects are sometimes problematic.

Prescription of drugs with potential adverse effects on cardiac conduction in Parkinson's disease

BACKGROUND Epidemiological studies report an association of ventricular arrhythmias with medication through prolongation of the cardiac QT interval. This has implications in the management of Parkinsons disease, as commonly prescribed drugs for non-motor symptoms and comorbidities have QT prolonging potential. OBJECTIVES To review prescribed medication in Parkinsons disease patients, in particular the use of drugs that may prolong the cardiac QT interval, in relation to other risk factors for QT prolongation. METHODS Medication prescription and doses, presence of underlying cardiac disease, patient age, and sex were recorded in a cross-sectional sample of 360 current PD patients attending two district and one regional specialist hospital-based movement disorder clinics. RESULTS We sampled 360 consecutive patients with PD, median age 66.5 years (interquartile range 58.5-74.8) and median disease duration 4.2 years (interquartile range 1.2-8.0 years). 125 (34.7%) were taking one or more drugs with definite potential to prolong QT, including domperidone in 91 (25.2%), citalopram or escitalopram in 47 (13.1%), and concurrent antibiotics in 5 (1.3%). Cofactors increasing the risk for QT interval prolongation were: age over 60 years 71.7%, female sex 46.9%, and presence of cardiac disease 19.2%. In patients with combined risk factors, the rate of prescription of at least one definite QT prolonging drug was between 34.5 and 42.1%. CONCLUSIONS Combination therapy and comorbidity relevant to cardiac QT prolongation are common in patients with Parkinsons disease. Strategies to reduce the proportion of patients at risk from iatrogenic adverse cardiac events are warranted.

The progressive myoclonic epilepsies.

Progressive myoclonic epilepsies are a group of disorders characterised by a relentlessly progressive disease course until death; treatment-resistant epilepsy is just a part of the phenotype. This umbrella term encompasses many diverse conditions, ranging from Lafora body disease to Gauchers disease. These diseases as a group are important because of a generally poor response to antiepileptic medication, an overall poor prognosis and inheritance risks to siblings or offspring (where there is a proven genetic cause). A correct diagnosis also helps patients and their families to accept and understand the nature of their disease, even if incurable. Here, we discuss the phenotypes of these disorders and summarise the relevant specific investigations to identify the underlying cause.

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.

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.