Jacquelyn J. Cragg

Longitudinal progression of sporadic Parkinson's disease: a multi-tracer positron emission tomography study

Parkinsons disease is a heterogeneous disorder with multiple factors contributing to disease initiation and progression. Using serial, multi-tracer positron emission tomography imaging, we studied a cohort of 78 subjects with sporadic Parkinsons disease to understand the disease course better. Subjects were scanned with radiotracers of presynaptic dopaminergic integrity at baseline and again after 4 and 8 years of follow-up. Non-linear multivariate regression analyses, using random effects, of the form BP(ND)(t) or K(occ)(t) = a*e((-)(bt)(-d)(A) + c, where BP(ND) = tracer binding potential (nondispaceable), K(OCC) = tracer uptake constant a, b, c and d are regression parameters, t is the symptom duration and A is the age at onset, were utilized to model the longitudinal progression of radiotracer binding/uptake. We found that the initial tracer binding/uptake was significantly different in anterior versus posterior striatal subregions, indicating that the degree of denervation at disease onset was different between regions. However, the relative rate of decline in tracer binding/uptake was similar between the striatal subregions. While an antero-posterior gradient of severity was maintained for dopamine synthesis, storage and reuptake, the asymmetry between the more and less affected striatum became less prominent over the disease course. Our study suggests that the mechanisms underlying Parkinsons disease initiation and progression are probably different. Whereas factors responsible for disease initiation affect striatal subregions differently, those factors contributing to disease progression affect all striatal subregions to a similar degree and may therefore reflect non-specific mechanisms such as oxidative stress, inflammation or excitotoxicity.

Age-specific progression of nigrostriatal dysfunction in Parkinson's disease

To investigate in vivo the impact of age on nigrostriatal dopamine dysfunction in Parkinsons disease (PD).

Cardiovascular disease and spinal cord injury: Results from a national population health survey

Objective: To evaluate the association between cardiovascular disease (CVD) and spinal cord injury (SCI) in a large representative sample. Methods: Data were compiled from more than 60,000 individuals from the 2010 cycle of the cross-sectional Canadian Community Health Survey (CCHS). Multivariable logistic regression analysis was conducted to examine this relationship, adjusting for confounders and using probability weighting to account for the CCHS sampling method. Results: After adjusting for age and sex, SCI was associated with a significant increased odds of heart disease (adjusted odds ratio [OR] = 2.72, 95% confidence interval [CI] 1.94–3.82) and stroke (adjusted OR = 3.72, 95% CI 2.22–6.23). Conclusions: These remarkably heightened odds highlight the exigent need for targeted interventions and prevention strategies addressing modifiable risk factors for CVD in individuals with SCI.

Spinal cord injury and type 2 diabetes: Results from a population health survey

Objective: The objective of this study was to evaluate the association between spinal cord injury (SCI) and type 2 diabetes in a large representative sample and to determine whether an association exists irrespective of known risk factors for type 2 diabetes. Methods: Data were obtained on 60,678 respondents to the Statistics Canada 2010 Cycle of the cross-sectional Canadian Community Health Survey. Multivariable logistic regression, incorporating adjustment for confounders and probability weights to account for the Canadian Community Health Survey sampling method, was conducted to quantify this association. Results: After adjustment for both sex and age, SCI was associated with a significant increased odds of type 2 diabetes (adjusted odds ratio = 1.66, 95% confidence interval 1.16–2.36). These heightened odds persisted after additional adjustment for smoking status, hypertension status, body mass index, daily physical activity, alcohol intake, and daily consumption of fruits and vegetables (fully adjusted odds ratio = 2.45, 95% confidence interval 1.34–4.47). Conclusions: There is a strong association between SCI and type 2 diabetes, which is not explained by known risk factors for type 2 diabetes.

Management of Cardiovascular Disease Risk Factors in Individuals with Chronic Spinal Cord Injury: An Evidence-Based Review

Clinical scenario: A 37-year-old man suffered a complete spinal cord injury (C8, American Spinal Injury Association Impairment Scale [ASIA] score A) 10 years ago in a car accident. Should primary prevention of cardiovascular disease be a priority in this patient? In order to answer this question, we performed a systematic review of the literature to inform an evidence-based clinical review. The objective was to provide a comprehensive and up-to-date review of the clinical management of cardiovascular disease (CVD) and risk factors for individuals with spinal cord injury (SCI). Comprehensive literature searches were performed. The quality of each study was assessed using the Physiotherapy Evidence Database Scale for randomized controlled trials, and the Downs and Black Scale for all other studies. Levels of evidence were assigned using a modified version of Sacketts scale. Our findings indicate that CVD is a critical issue in individuals with chronic SCI. Almost all risk factors for CVD are amplified in individuals with SCI, including physical inactivity, dyslipidemia, blood pressure irregularities, abnormal glycemic control, and chronic inflammation. However, there is a paucity of high-quality literature with respect to treatment outcomes in SCI-specific study populations (a total of 22 intervention studies in all of these categories combined) that allow for the development of evidence-informed clinical practice recommendations. These limitations notwithstanding, we present a series of contemporary practice suggestions with regard to CVD event risk modification in SCI patients. For optimal outcomes, health care providers should be cognizant of these heightened CVD risk factors and the resultant increased CVD morbidity and mortality in SCI patients. Despite the absence of high-quality evidence-based treatment strategies, clinicians should re-examine their own CVD risk factor treatment strategies to better reflect contemporary practice in similar high-CVD-event-risk patients and populations.

The Nature of Progression in Parkinson’s Disease: An Application of Non-Linear, Multivariate, Longitudinal Random Effects Modelling

Background To date, statistical methods that take into account fully the non-linear, longitudinal and multivariate aspects of clinical data have not been applied to the study of progression in Parkinson’s disease (PD). In this paper, we demonstrate the usefulness of such methodology for studying the temporal and spatial aspects of the progression of PD. Extending this methodology further, we also explore the presymptomatic course of this disease. Methods Longitudinal Positron Emission Tomography (PET) measurements were collected on 78 PD patients, from 4 subregions on each side of the brain, using 3 different radiotracers. Non-linear, multivariate, longitudinal random effects modelling was applied to analyze and interpret these data. Results The data showed a non-linear decline in PET measurements, which we modelled successfully by an exponential function depending on two patient-related covariates duration since symptom onset and age at symptom onset. We found that the degree of damage was significantly greater in the posterior putamen than in the anterior putamen throughout the disease. We also found that over the course of the illness, the difference between the less affected and more affected sides of the brain decreased in the anterior putamen. Younger patients had significantly poorer measurements than older patients at the time of symptom onset suggesting more effective compensatory mechanisms delaying the onset of symptoms. Cautious extrapolation showed that disease onset had occurred some 8 to 17 years prior to symptom onset. Conclusions Our model provides important biological insights into the pathogenesis of PD, as well as its preclinical aspects. Our methodology can be applied widely to study many other chronic progressive diseases.

Meta-analysis of placebo responses in central neuropathic pain: impact of subject, study, and pain characteristics

Abstract The placebo response is a complex construct related to psychobiological effects, as well as natural history and regression to the mean. Moreover, patient and study design characteristics have also been proposed as significantly affecting placebo responses. The aim of the current investigation was to identify factors that contribute to variable placebo responses in clinical trials involving individuals with central neuropathic pain. To this end, we performed a systematic review and meta-analysis of placebo-controlled trials examining pharmacological and noninvasive brain stimulation interventions for central neuropathic pain. Study design, subject characteristics, and pain ratings for the placebo group were extracted from each trial. Pooling of results and identification of moderating factors were carried out using random effects meta-analysis and meta-regression techniques. A total of 39 published trials met the inclusion criteria (spinal cord injury, n = 26; stroke, n = 6; multiple sclerosis, n = 7). No significant publication bias was detected. Overall, there was a significant effect for placebo to reduce central pain (−0.64, CI: −0.83 to −0.45). Smaller placebo responses were associated with crossover-design studies, longer pain duration, and greater between-subject baseline pain variability. There were no significant effects for neurological condition (stroke vs multiple sclerosis vs spinal cord injury) or the type of intervention (eg, pharmacological vs noninvasive brain stimulation). In a planned subanalysis, the severity of damage in the spinal cord also had no significant effect on the placebo response. Further study is warranted to identify factors that may explain the impact of pain duration on the placebo response at the individual subject level.

Effects of Pain and Pain Management on Motor Recovery of Spinal Cord–Injured Patients: A Longitudinal Study

Background. Approximately 60% of patients suffering from acute spinal cord injury (SCI) develop pain within days to weeks after injury, which ultimately persists into chronic stages. To date, the consequences of pain after SCI have been largely examined in terms of interfering with quality of life. Objective. The objective of this study was to examine the effects of pain and pain management on neurological recovery after SCI. Methods. We analyzed clinical data in a prospective multicenter observational cohort study in patients with SCI. Using mixed effects regression techniques, total motor and sensory scores were modelled at 1, 3, 6, and 12 months postinjury. Results. A total of 225 individuals were included in the study (mean age: 45.8 ± 18 years, 80% male). At 1 month postinjury, 28% of individuals with SCI reported at- or below-level neuropathic pain. While pain classification showed no effect on neurological outcomes, individuals administered anticonvulsant medications at 1 month postinjury showed significant reductions in pain intensity (2 points over 1 year; P < .05) and greater recovery in total motor scores (7.3 points over 1 year; P < .05). This drug effect on motor recovery remained significant after adjustment for injury level and injury severity, pain classification, and pain intensity. Conclusion. While initial pain classification and intensity did not reveal an effect on motor recovery following acute SCI, anticonvulsants conferred a significant beneficial effect on motor outcomes. Early intervention with anticonvulsants may have effects beyond pain management and warrant further studies to evaluate the therapeutic effectiveness in human SCI.

Neuropathic pain, depression, and cardiovascular disease: a national multicenter study.

Background: Individuals with spinal cord injury (SCI) have a more than twofold increased risk of heart disease and stroke compared with able-bodied individuals. The increased risk appears to be in excess of the risk conferred by several well-established risk factors, including diabetes, hypertension, and sex. This raises the question whether other factors, secondary to SCI, are also contributing to the development of cardiovascular disease (CVD). Two potential factors associated with SCI and CVD are pain and depression. Both are frequently reported among individuals with SCI, develop in the acute stages of injury, and are commonly described as severe. Therefore, the primary aim of this study was to examine the relationship between pain (and types of pain) and depression with CVD among individuals with SCI. Methods: A total of 1,493 individuals (referred sample) with chronic SCI participated in a self-report cross-sectional multicenter Canada-wide survey from 2011-2012 (mean age ± standard deviation: 49.6 ± 13.9 years). Results: After adjustment for age, sex, and injury characteristics, neuropathic pain and depression were significantly and independently associated with CVD (adjusted odds ratio and 95% confidence interval: 2.27 (1.21, 4.60) for neuropathic pain; 4.07 (2.10, 7.87) for depression). In contrast to neuropathic pain, non-neuropathic pain was not significantly associated with CVD (p = 0.13). Conclusion: In conclusion, these data illustrate important interrelationships between secondary complications following SCI, as well as raise the possibility of neuropathic pain (versus nociceptive pain) as a novel and emerging risk factor for CVD.

Pearls & Oy-sters: Transient Horner syndrome associated with autonomic dysreflexia

Autonomic dysreflexia is a potentially life-threatening condition that occurs in individuals with high thoracic and cervical spinal cord injuries (SCIs) and is characterized by severe episodic hypertension.