Selecting the best patient groups for clinical trials: insights from the CamPaIGN study of Parkinson’s disease

This post was inspired by a talk given by Prof Roger Barker, to whom all credit for the ideas below must be attributed. His group are also doing some very exciting work on cell based therapies and viral-RNA based therapies for PD which I plan to write about in the future.
 

In addition to identifying PD as early as possible, being able to identify those with a more severe, rapidly-progressing form of the disease would help with deciding who should be entered into clinical trials of disease-modifying therapies.

Longitudinal studies of patients with PD (such as the CamPaIGN study) have shown that while some patients with PD may have ‘good’ outcomes (no dementia or postural instability) even 10 years after their diagnosis, others may progress much more rapidly to getting dementia or postural instability [1].

This second group with a more rapidly-progressing underlying disease process, would be the ideal group with which to trial new potentially disease-modifying therapies, whereas those with a more ‘benign’ form of PD are likely to do well with dopaminergic based therapies.

Therefore, being able to predict whether a patient will have a benign or rapidly-progressing disease course is important, not only for patients’ and their families’ own information, but also to optimise who gets what treatment.

Luckily, the CamPaIGN study managed to identify a few factors which predict a rapid progression to Parkinson’s disease dementia, including:

• Age 
• Poor semantic fluency [1] – reduced ability to name as many animals as possible from memory in 90 seconds
• Poor overlapping pentagon drawing – poor ability to replicate the overlapping
• Having two copies of the H1 variant of the gene ‘MAPT’. This encodes a protein called ‘Tau’ which has been implicated in a number of neurodegenerative diseases, including Alzheimer’s [2]
• Having a single abnormal copy of the GBA gene. ALL the patients with a single GBA mutation in the CamPaiGN study developed dementia by 8 years. (GBA is a gene which causes Gaucher’s disease when two mutated copies are inherited. People with a single mutation do not develop Gaucher’s and are otherwise healthy, they are known to have an increased risk of developing PD)

 

This is a great example of how epidemiological evidence can inform clinical practice (by allowing doctors to more accurately assess prognosis), add to our understanding of the mechanisms of disease (in this case, by suggest a role for Tau in the pathology of Parkinson’s disease dementia) and help optimise our efforts to find new treatments for a disease (by helping to select the best patients for trials of new therapies).

References:

1. Williams-Gray CH, Mason SL, Evans JR, Foltynie T, Brayne C, Robbins TW, Barker RA: The CamPaIGN study of Parkinson's disease: 10-year outlook in an incident population-based cohort. J Neurol Neurosurg Psychiatry 2013.

2. Goris A, Williams-Gray CH, Clark GR, Foltynie T, Lewis SJ, Brown J, Ban M, Spillantini MG, Compston A, Burn DJ, et al.: Tau and alpha-synuclein in susceptibility to, and dementia in, Parkinson's disease. Ann Neurol 2007, 62:145-153.

Screening for early detection of parkinsonism using a self-administered questionnaire: A cross-sectional epidemiologic study

Neurotoxicology. 2013 Sep 12. pii: S0161-813X(13)00134-4. doi: 10.1016/j.neuro.2013.08.010. [Epub ahead of print]

Lundin JI, Checkoway H, Criswell SR, Hobson A, Harris RC, Swisher LM, Evanoff BA, Racette BA.

Source

University of Washington, Department of Environmental and Occupational Health Sciences, Seattle, WA, USA. Electronic address: jlundin2@uw.edu.

Abstract

BACKGROUND:

Manganese (Mn) is a common component of welding fume. Exposure to Mn fume has been associated with parkinsonism. A simple and reliable screening tool to evaluate Mn exposed workers for neurotoxic injury would have broad occupational health application.

METHODS:

This study investigated 490 occupational welders recruited from a trade union list. Subjects were examined by a movement disorders specialist using the Unified Parkinson Disease Rating Scale motor subsection 3 (UPDRS3). Parkinsonism, intermediate, and normal groups were defined as UPDRS3 score ≥15, 6-15, and <6, respectively. Workers completed a health status questionnaire (PDQ39) and a Parkinson's disease (PD) Symptoms Questionnaire. Areas under receiver operator curve (AUC) were analyzed based on these scores, adjusted for age, smoking, race, gender, and neurologist, using normal as the reference.

RESULTS:

The AUC was 0.79 (95% confidence interval [CI]=0.73-0.84) for PDQ39 and 0.78 (95% CI=0.72-0.85) for PD Symptoms Questionnaire score. At 70% sensitivity, the specificity for PDQ39 score and PD Symptoms Questionnaire score for the prediction of parkinsonism was 73.1% and 80.1%, respectively.

CONCLUSIONS:

These results suggest the questionnaires have reasonably good sensitivity and specificity to predict parkinsonism in Mn exposed workers. These questionnaires could be a valuable first step in a tiered screening approach for Mn exposed workers.

The nucleus basalis of Meynert: A new target for deep brain stimulation in dementia?

Neurosci Biobehav Rev. 2013 Sep 11. pii: S0149-7634(13)00206-6. doi: 10.1016/j.neubiorev.2013.09.003. [Epub ahead of print]

Gratwicke J, Kahan J, Zrinzo L, Hariz M, Limousin P, Foltynie T, Jahanshahi M.

Source

Unit of Functional Neurosurgery, Sobell Department of Motor Neuroscience and Movement Disorders, UCL Institute of Neurology, Queen Square, London, UK, WC1N 3BG.

Abstract

Dementia is a major cause of disability amongst the elderly and represents a serious global health issue. Current treatments for dementia are limited; at best they provide inadequate symptomatic relief. In contrast, there are a plethora of approaches that provide symptomatic relief for abnormalities of movement including surgical approaches. Deep brain stimulation has been used successfully to directly alter processing in neural networks and thereby improve movement functions. Here we describe the anatomy, intrinsic organization and connectivity of the cholinergic nucleus basalis of Meynert, a basal forebrain structure implicated in cognitive functions including memory, attention, arousal and perception. A significant body of evidence suggests that degeneration of the nucleus and its cortical projections underlies the cognitive decline seen in dementia. We review this evidence and postulate that deep brain stimulation to this nucleus may be able to improve specific cognitive functions. This could represent a novel treatment strategy for some dementias in carefully selected individuals. Controlled trials of deep brain stimulation of the nucleus basalis of Meynert for Parkinson's disease dementia and Alzheimer's disease are required to evaluate potential efficacy and the mechanisms of possible cognitive changes.

Quantitative wearable sensors for objective assessment of Parkinson's disease

Mov Disord. 2013 Sep 12. doi: 10.1002/mds.25628. [Epub ahead of print]

Maetzler W, Domingos J, Srulijes K, Ferreira JJ, Bloem BR.

Source

Hertie Institute for Clinical Brain Research, Department of Neurodegeneration, Center of Neurology, University of Tuebingen, Tuebingen, Germany; German Center for Neurodegenerative Diseases (DZNE), Tuebingen, Germany.

Abstract

There is a rapidly growing interest in the quantitative assessment of Parkinson's disease (PD)-associated signs and disability using wearable technology. Both persons with PD and their clinicians see advantages in such developments. Specifically, quantitative assessments using wearable technology may allow for continuous, unobtrusive, objective, and ecologically valid data collection. Also, this approach may improve patient-doctor interaction, influence therapeutic decisions, and ultimately ameliorate patients' global health status. In addition, such measures have the potential to be used as outcome parameters in clinical trials, allowing for frequent assessments; eg, in the home setting. This review discusses promising wearable technology, addresses which parameters should be prioritized in such assessment strategies, and reports about studies that have already investigated daily life issues in PD using this new technology.

Rotigotine for anxiety during wearing-off in Parkinson's disease with dementia

Aging Clin Exp Res. 2013 Sep 10. [Epub ahead of print]

Fanciulli A, Assogna F, Caltagirone C, Spalletta G, Pontieri FE.

Source

Dipartimento di Neuroscienze, Salute Mentale e Organi di Senso - NeSMOS, "Sapienza" Università di Roma, Via di Grottarossa, 1035, 00189, Rome, Italy.

Abstract

BACKGROUND:

Wearing-off (WO) refers to the exacerbation of motor and/or non-motor symptoms of Parkinson's disease at the end of dose of dopaminergic medications. Treatment of WO is based on modifying drug schedule, meal timetable and/or increasing dopamine replacement therapy. In advanced and/or demented patients, management of WO is often limited by scarce compliance and by cognitive, psychiatric and dysautonomic side-effects that may accompany increased dopaminergic stimulation.

METHODS:

Here, we report 2 patients suffering from Parkinson's disease with dementia, who experienced anxiety as non-motor symptom of WO under stable levodopa therapy. In both cases, transdermal rotigotine (4 mg/day) was added to the original dopaminergic therapy.

RESULTS:

Rotigotine proved beneficial on symptoms of anxiety in both patients, without worsening cognitive and behavioral symptoms. During the 9-month follow-up period, there was a slight improvement of motor impairment, with no worsening of drug-related dyskinesia.

CONCLUSIONS:

These preliminary results suggest that rotigotine at low dose might improve non-motor symptoms of WO in elderly patients suffering from Parkinson's disease with dementia, without raising major safety issues.

Quality of life in Parkinson's disease caregivers: the contribution of personality traits

Biomed Res Int. 2013;2013:151872. doi: 10.1155/2013/151872. Epub 2013 Aug 19.

Tew EH, Naismith SL, Pereira M, Lewis SJ.

Source

Parkinson's Disease Research Clinic, Brain and Mind Research Institute, University of Sydney, Sydney, NSW 2050, Australia.

Abstract

Parkinson's disease imposes significant demands not only on patients but also on those people living and caring for them, who often have a reduction in their quality of life. The factors that may ameliorate these effects, such as an individual's personality, are not understood. Therefore, the aim of this study was to look at the relative contribution of caregiver personality on their quality of life, specifically attempting to identify those traits, which may be protective or harmful. Two hundred and seventy-four caregivers of patients with Parkinson's disease were included in this study. Caregivers were given questionnaires to complete, including the Big Five Inventory and the World Health Organisation Quality of Life BREF version. Univariate correlations demonstrated that depression and anxiety were the largest predictors of reduced quality of life amongst caregivers. However, after controlling for these potential confounds, conscientiousness was associated with enhanced psychological quality of life and openness positively predicted benefits in the environmental domain. Neuroticism was associated with reduced quality of life in the psychological domain. Thus, screening for neuroticism may help identify those caregivers who would benefit from intervention strategies, which could in the long term help reduce the need for nursing home placement of Parkinson's disease patients.

Motor phenotype and magnetic resonance measures of basal ganglia iron levels in Parkinson's disease

Parkinsonism Relat Disord. 2013 Aug 29. pii: S1353-8020(13)00305-2. doi: 10.1016/j.parkreldis.2013.08.011. [Epub ahead of print]

Bunzeck N, Singh-Curry V, Eckart C, Weiskopf N, Perry RJ, Bain PG, Düzel E, Husain M.

Source

Department of Systems Neuroscience, University Medical Center Hamburg-Eppendorf, Germany. 

Abstract

BACKGROUND:

In Parkinson's disease the degree of motor impairment can be classified with respect to tremor dominant and akinetic rigid features. While tremor dominance and akinetic rigidity might represent two ends of a continuum rather than discrete entities, it would be important to have non-invasive markers of any biological differences between them in vivo, to assess disease trajectories and response to treatment, as well as providing insights into the underlying mechanisms contributing to heterogeneity within the Parkinson's disease population.

METHODS:

Here, we used magnetic resonance imaging to examine whether Parkinson's disease patients exhibit structural changes within the basal ganglia that might relate to motor phenotype. Specifically, we examined volumes of basal ganglia regions, as well as transverse relaxation rate (a putative marker of iron load) and magnetization transfer saturation (considered to index structural integrity) within these regions in 40 individuals.

RESULTS:

We found decreased volume and reduced magnetization transfer within the substantia nigra in Parkinson's disease patients compared to healthy controls. Importantly, there was a positive correlation between tremulous motor phenotype and transverse relaxation rate (reflecting iron load) within the putamen, caudate and thalamus.

CONCLUSIONS:

Our findings suggest that akinetic rigid and tremor dominant symptoms of Parkinson's disease might be differentiated on the basis of the transverse relaxation rate within specific basal ganglia structures. Moreover, they suggest that iron load within the basal ganglia makes an important contribution to motor phenotype, a key prognostic indicator of disease progression in Parkinson's disease.

Influence of Single Nucleotide Polymorphisms in COMT , MAO-A and BDNF Genes on Dyskinesias and Levodopa Use in Parkinson's Disease

Neurodegener Dis. 2013 Sep 5. [Epub ahead of print]

Cheshire P, Bertram K, Ling H, O'Sullivan SS, Halliday G, McLean C, Bras J, Foltynie T, Storey E, Williams DR.

Source

Department of Medicine (Neuroscience), Monash University (Alfred Hospital), Melbourne, Vic., Australia.

Abstract

Background: Clinical heterogeneity in the development of levodopa-induced dyskinesias (LID) suggests endogenous factors play a significant role in determining their overall prevalence. Objective: We hypothesised that single nucleotide polymorphisms (SNPs) in specific genes may result in a clinical phenotype conducive to an increased risk of LID. Methods: We examined the influence of SNPs in the catechol-O-methyltransferase (COMT), monoamine oxidase A (MAO-A) and brain-derived neurotrophic factor (BDNF) genes on LID in a cohort of 285 pathologically confirmed Parkinson's disease patients, using data from their complete disease course. Results: Dyskinetic patients demonstrated younger age at disease onset (60.3 vs. 66.4 years, p < 0.0001), a longer disease duration (17.0 vs. 12.0 years, p < 0.0001) and a higher maximum daily levodopa equivalent dose (LED; 926.7 vs. 617.1 mg/day, p < 0.0001) than patients without dyskinesias. No individual SNP was found to influence prevalence or time to onset of dyskinesias, including after adjustment for known risk factors. We observed that patients carrying alleles conferring both high COMT activity and increased MAO-A mRNA expression received significantly higher maximum and mean daily LEDs than those with low enzyme activity/mRNA expression (max LED: 835 ± 445 vs. 508 ± 316 mg; p = 0.0056, mean LED: 601 ± 335 vs. 398 ± 260 mg; p = 0.025). Conclusions: Individual SNPs in BDNF, COMT and MAO-A genes did not influence prevalence or time to onset of dyskinesias in this cohort. The possibility that combined COMT and MAO-A genotype is a significant factor in determining an individual's lifetime levodopa exposure warrants further investigation.

Association Between Early-Onset Parkinson Disease and 22q11.2 Deletion Syndrome: Identification of a Novel Genetic Form of Parkinson Disease and Its Clinical Implications

Nancy J. Butcher, Tim-Rasmus Kiehl, Lili-Naz Hazrati, Eva W. C. Chow, Ekaterina Rogaeva, Anthony E. Lang, Anne S. Bassett

JAMA Neurol. Published online September 09, 2013

Importance   Clinical case reports of parkinsonism co-occurring with hemizygous 22q11.2 deletions and the associated multisystem syndrome, 22q11.2 deletion syndrome (22q11.2DS), suggest that 22q11.2 deletions may lead to increased risk of early-onset Parkinson disease (PD). The frequency of PD and its neuropathological presentation remain unknown in this common genetic condition.

Objective   To evaluate a possible association between 22q11.2 deletions and PD.

Design, Setting, and Participants   An observational study of the occurrence of PD in the world’s largest cohort of well-characterized adults with a molecularly confirmed diagnosis of 22q11.2DS (n = 159 [6 with postmortem tissue]; age range, 18.1-68.6 years) was conducted in Toronto, Ontario, Canada. Rare postmortem brain tissue from individuals with 22q11.2DS and a clinical history of PD was investigated for neurodegenerative changes and compared with that from individuals with no history of a movement disorder.

Main Outcomes and Measures   A clinical diagnosis of PD made by a neurologist and neuropathological features of PD.

Results   Adults with 22q11.2DS had a significantly elevated occurrence of PD compared with standard population estimates (standardized morbidity ratio = 69.7; 95% CI, 19.0-178.5). All cases showed early onset and typical PD symptom pattern, treatment response, and course. All were negative for family history of PD and known pathogenic PD-related mutations. The common use of antipsychotics in patients with 22q11.2DS to manage associated psychiatric symptoms delayed diagnosis of PD by up to 10 years. Postmortem brain tissue revealed classic loss of midbrain dopaminergic neurons in all 3 postmortem 22q11.2DS-PD cases. Typical α-synuclein–positive Lewy bodies were present in the expected distribution in 2 cases but absent in another.

Conclusions and Relevance   These findings suggest that 22q11.2 deletions represent a novel genetic risk factor for early-onset PD with variable neuropathological presentation reminiscent of LRRK2-associated PD neuropathology. Individuals with early-onset PD and classic features of 22q11.2DS should be considered for genetic testing, and those with a known 22q11.2 deletion should be monitored for the development of parkinsonian symptoms. Molecular studies of the implicated genes, including DGCR8, may help shed light on the underlying pathophysiology of PD in 22q11.2DS and idiopathic PD.

Comparison of once-daily versus twice-daily combination of Ropinirole prolonged release in Parkinson's disease

BMC Neurol. 2013 Sep 2;13(1):113. [Epub ahead of print]

Yun JY, Kim HJ, Lee JY, Kim YE, Kim JS, Kim JM, Jeon BS.

Abstract

BACKGROUND:

Ropinirole prolonged release (RPR) is a once-daily formulation. However, there may be individual pharmacokinetic differences so that multiple dosing may be preferred in some individuals. This study compares once-daily and twice-daily RPR in patients with Parkinson's disease.

METHODS:

This study was an open-label crossover study. We enrolled Parkinson's disease patients on dopamine agonist therapy with unsatisfactory control such as motor fluctuation, dyskinesia and sleep-related problems. Agonists were switched into equivalent dose of RPR. Subjects were consecutively enrolled into either once-daily first or twice-daily first groups, and received the same amount of RPR in a single and two divided dosing for 8 weeks respectively in a crossover manner without a washout period.The primary outcome was a questionnaire of the preference completed by patients in the last visit. The secondary outcome measures included the Unified Parkinson's Disease Rating Scale part 3 (mUPDRS), Hoehn and Yahr stage (H&Y); sleep questionnaire including overall quality of sleep, nocturnal off symptoms and early morning symptoms; Epworth Sleep Scale (ESS); compliances and patient global impression (PGI).

RESULTS:

A total of 82 patients were enrolled and 61 completed the study. 31 patients preferred twice-daily regimen, 17 preferred the once-daily regimen, and 13 had no preference. Their mean mUPDRS, H&Y, ESS, sleep quality, compliance and adverse events were not statistically different in both regimens. PGI-improvement on wearing off defined was better in twice-daily dosing regimen.

CONCLUSION:

RPR is a once-daily formulation, but multiple dosing was preferred in many patients. Multiple dosing of RPR might be a therapeutic option if once-daily dosing is unsatisfactory.Trial registration: This study is registered with ClinicalTrials.gov, number NCT00986245.

Motor fluctuations and Helicobacter pylori in Parkinson's disease

J Neurol. 2013 Sep 4. [Epub ahead of print]

Rahne KE, Tagesson C, Nyholm D.

Source

NeuroCenter Saint Göran Hospital, Stockholm, Sweden.

Abstract

The presence of Helicobacter pylori (HP) in the gastrointestinal tract may limit the absorption of levodopa. The objectives of this study were to investigate whether HP infection may affect the clinical response to levodopa as well as levodopa dose requirement in patients with Parkinson's disease (PD) as well as to investigate whether HP infection may affect plasma levels of vitamin B12, folic acid, and homocysteine. Seventy-five patients with PD diagnosed at least 4 years ago were included. Symptom fluctuations were assessed by UPDRS-IV and the WOQ9 wearing-off-scale. Plasma levels of vitamin B12, folic acid, and homocysteine were analyzed. Screening for HP was performed with a 13C-labeled urea breath test (Diabact UBT). A propensity-matched analysis was made where each patient in the HP-infected group was matched with one patient in the non-infected group with respect to age and gender. Of the 75 included patients, 20 were HP infected (27 %). Median Hoehn & Yahr scores were 3 in both HP infected patients and the matched group (n = 20). HP-infected patients had decreased "complications of therapy" with average total UPDRS-IV score of 4.8 ± 3.0 vs. 7.7 ± 3.8 (p < 0.05), despite no significant difference in levodopa equivalent dose. Wearing-off and sleep disturbance were significantly less common in the HP group (p < 0.05). There were no differences regarding vitamin B12, folic acid, or homocysteine values. HP infection in patients with PD may result in a decreased occurrence of symptom fluctuations according to this small study. This finding may be due to altered absorption of levodopa in the gastrointestinal tract in patients with HP infection, but further studies are required.