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

J Neurol Neurosurg Psychiatry. 2013 Jul 4. [Epub ahead of print]

Noyce AJ, Bestwick JP, Silveira-Moriyama L, Hawkes CH, Knowles CH, Hardy J, Giovannoni G, Nageshwaran S, Osborne C, Lees AJ, Schrag A.

Source

Reta Lila Weston Institute of Neurological Studies, UCL Institute of Neurology, , London, UK.

Abstract

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.

Drug development in Parkinson's disease: From emerging molecules to innovative drug delivery systems.

Maturitas. 2013 Jul 1. pii: S0378-5122(13)00182-5. doi: 10.1016/j.maturitas.2013.05.019. [Epub ahead of print]

Garbayo E, Ansorena E, Blanco-Prieto MJ.

Source

Pharmacy and Pharmaceutical Technology Department, University of Navarra, Pamplona, Spain.

Abstract

Current treatments for Parkinson's disease (PD) are aimed at addressing motor symptoms but there is no therapy focused on modifying the course of the disease. Successful treatment strategies have been so far limited and brain drug delivery remains a major challenge that restricts its treatment. This review provides an overview of the most promising emerging agents in the field of PD drug discovery, discussing improvements that have been made in brain drug delivery for PD. It will be shown that new approaches able to extend the length of the treatment, to release the drug in a continuous manner or to cross the blood-brain barrier and target a specific region are still needed. Overall, the results reviewed here show that there is an urgent need to develop both symptomatic and disease-modifying treatments, giving priority to neuroprotective treatments. Promising perspectives are being provided in this field by rasagiline and by neurotrophic factors like glial cell line-derived neurotrophic factor. The identification of disease-relevant genes has also encouraged the search for disease-modifying therapies that function by identifying molecularly targeted drugs. The advent of new molecular and cellular targets like α-synuclein, leucine-rich repeat serine/threonine protein kinase 2 or parkin, among others, will require innovative delivery therapies. In this regard, drug delivery systems (DDS) have shown great potential for improving the efficacy of conventional and new PD therapy and reducing its side effects. The new DDS discussed here, which include microparticles, nanoparticles and hydrogels among others, will probably open up possibilities that extend beyond symptomatic relief. However, further work needs to be done before DDS become a therapeutic option for PD patients.

Drivers with Parkinson's disease: are the symptoms of PD associated with restricted driving practices?

J Neurol. 2013 Jul 3. [Epub ahead of print]

Crizzle AM, Myers AM, Roy EA, Almeida QJ.

Source

School of Public Health and Health Systems, Faculty of Applied Health Sciences, University of Waterloo, Waterloo, ON, N2L 3G1, Canada

Abstract

This study examined whether symptoms (motor, cognitive, vision, sleepiness, depression) of Parkinson's disease (PD) were associated with restricted driving practices. To quantify driving practices, electronic devices were installed in the vehicles of 27 drivers with PD (78 % men; M = 71.6, SD = 6.6; Unified Parkinson's Disease Rating Scale (UPDRS) motor score M = 30.1, SD = 8.6; disease duration M = 3.9, SD = 2.8 years) and 20 controls (80 % men; M = 70.6, SD = 7.9) for 2 weeks. Participants completed measures of sleepiness, depression, quality of life, and assessments of motor, cognitive and visual functions. The PD group had significantly slower brake response times (p < 0.05), poorer cognitive and quality of life scores (p < 0.01) and greater depression (p < 0.05) compared to controls. Slower reaction time was significantly related to reduced driving; specifically, fewer trips (r = -0.46; p < 0.05), distance (r = -0.54, p < 0.01) and duration at night (r = -0.58, p < 0.01). Better cognitive scores were associated with driving less often in difficult situations such as bad weather and rush hour (p < 0.05), as well as reduced speed on city streets, but only for the control group. While most drivers with PD rated their overall health as good or excellent, the five PD drivers who rated their health more poorly had significantly worse clinical symptoms (UPDRS motor scores, contrast sensitivity, depression, brake response time) and more restricted driving patterns. These findings show that drivers with PD who perceive their health poorly have greater symptomatology and were more likely to restrict their driving, possibly due to noticeable declines in multiple driving-related abilities.

Recent developments in biomarkers in Parkinson disease

Curr Opin Neurol. 2013 Aug;26(4):395-400. doi: 10.1097/WCO.0b013e3283633741.

Schapira AH.

Source

Department of Clinical Neurosciences, UCL Institute of Neurology, London, UK.

Abstract

PURPOSE OF REVIEW:

Parkinson disease is the second most common neurodegenerative disease after Alzheimer disease, and current demographic trends indicate a life-time risk approaching 4% and predict a doubling of prevalence by 2030. Strategies are being developed to apply recent advances in our understanding of the cause of Parkinson disease to the development of biomarkers that will enable the identification of at-risk individuals, enable early diagnosis and reflect the progression of disease. The latter will be particularly important for the testing of disease-modifying therapies. This review summarizes recent advances in Parkinson disease biomarker development.

RECENT FINDINGS:

Recent reports continue to reflect the application of a variety of clinical, imaging or biochemical measurements, alone or in combination, to general Parkinson disease populations. Probably the most promising is the assay of alpha-synuclein in the diagnosis and evolution of Parkinson disease. At present, detection techniques are still being refined, but once accurate and reproducible assays are available, it will be important to define the relationship of these to early diagnosis and progression. Alpha-synuclein concentrations may also be modulated by certain disease-modifying agents in development and so may represent a measure of their efficacy. It has to be accepted that no single measure currently fulfils all the necessary criteria for a biomarker in Parkinson disease, but combinations of measures are more likely to deliver benefit.

SUMMARY:

The Parkinson disease biomarker field is approaching a stage when certain combinations of clinical, imaging and biochemical measures may identify a proportion of individuals at risk for developing the disease. However, their general applicability may be limited. Attention is now turning to stratification of Parkinson disease into certain at-risk groups defined by genotype. The application of multimodal screening to these populations may be more rewarding in the short term.

Different β-amyloid binding patterns in Alzheimer and Parkinson diseases: It's the network!

Neurology. 2013 Jul 3. [Epub ahead of print]

Eidelberg D, Martin W.

Source

From the Center for Neurosciences (D.E.), The Feinstein Institute for Medical Research, Manhasset, NY; and the Department of Medicine (Neurology) (W.M.), University of Alberta, Edmonton, Canada.

Abstract

11C-Pittsburgh compound B (PiB) PET is a sensitive and increasingly popular imaging tool for assessing the deposition of fibrillar β-amyloid aggregates in the brains of living patients with Alzheimer disease (AD). Increased cortical PiB binding also occurs in dementia with Lewy bodies, but rarely in cognitively impaired individuals with Parkinson disease (PD).1,2 To date, most PiB PET studies have focused on identifying significant group differences in radiotracer binding in single brain regions or in the cortex overall. However, recent evidence suggests that the deposition of protein aggregates in neurodegenerative disorders evolves at the systems level, with involvement of discrete sets of interconnected brain regions.3,4 In this regard, techniques of pattern analysis based upon principal component analysis (PCA) and other multivariate procedures are increasingly used to quantify disease-related circuit changes in functional brain images.5.

Depressive symptoms in Parkinson's disease are related to reduced [123I]FP-CIT binding in the caudate nucleus

J Neurol Neurosurg Psychiatry. 2013 Jun 29. [Epub ahead of print]

Vriend C, Raijmakers P, Veltman DJ, van Dijk KD, van der Werf YD, Foncke EM, Smit JH, Berendse HW, van den Heuvel OA.

Source

Department of Psychiatry, VU University Medical Center, , Amsterdam, The Netherlands.

Abstract

BACKGROUND:

Depression is a common neuropsychiatric symptom in Parkinson's disease (PD). In previous research, PD-related depression was associated with striatal dopaminergic deficits, presumably due to degeneration of brainstem dopaminergic projections. Segregated areas of the striatum are crucially involved in various parallelly arranged cortical-striatal-thalamocortical circuits and serve functions in, among others, motor control or emotion. This suggests regional specificity of dopaminergic deficits in the striatum in motor and depressive symptoms in PD.

METHODS:

In this cross-sectional retrospective study, we correlated severity scores of depressive and motor symptoms in 100 non-demented PD patients (median Hoehn & Yahr stage: 2) with dopamine loss in specific regions of the striatum as measured by [123I]FP-CIT SPECT tracer binding to the dopamine transporter (DaT).

RESULTS:

Depressive symptoms were related to lower DaT binding in the right caudate nucleus, while motor symptoms were associated with decreased DaT binding in the right putamen. This double dissociation was most pronounced in early-stage PD patients.

CONCLUSIONS:

These results suggest that depressive symptoms in PD are associated with dopamine loss in the caudate nucleus, possibly related to degeneration of dopaminergic projections from the ventral tegmental area, while motor symptoms are associated with low dopamine signalling to the putamen and loss of nigrostriatal projections. This is consistent with the neuroanatomy of partially segregated cortical-striatal-thalamocortical circuits and supports the role of dysfunctional associative and motivational circuits in PD-related depression.

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Neuropathy in Parkinson's Disease Patients with Intestinal Levodopa Infusion versus Oral Drugs

PLoS One. 2013 Jun 20;8(6):e66639. Print 2013.

Jugel C, Ehlen F, Taskin B, Marzinzik F, Müller T, Klostermann F.

Source

Department of Neurology, Charité - University Medicine, Campus Benjamin Franklin, Berlin, Germany.

Abstract

BACKGROUND:

Severe polyneuropathy has been observed in a number of patients treated for Parkinson's disease with Levodopa/Carbidopa intestinal gel infusion. This may reflect a rare individual complication or a systematic side effect.

OBJECTIVE:

To investigate whether peripheral nerve function differed between patients with oral treatment versus Levodopa/Carbidopa intestinal gel infusion.

METHODS:

In an observational design, data from median, tibial, and peroneal neurography were prospectively assessed and compared between patients with conventional drug treatment (n = 15) and with Levodopa/Carbidopa intestinal gel infusion (n = 15). The groups were matched for age and disease duration. In view of the medical risk profile for polyneuropathy, comorbidity and basic serological parameters were assessed.

RESULTS:

Axonal neuropathy was common in both patient groups. However, although group differences in risk factors for polyneuropathy were not evident, neurographic abnormalities were more severe in the patients treated with Levodopa/Carbidopa intestinal gel infusion than in the orally treated patients. In the group with Levodopa/Carbidopa intestinal gel infusion, the degree of neuropathic change correlated with weight lost since therapy initiation and with the drug dose. In contrast to the axonal abnormalities, conduction velocity was found normal in both groups.

CONCLUSION:

The results are compatible with the promotion of axonal neuropathy by Levodopa/Carbidopa intestinal gel infusion. This could be due to the intrinsically high levodopa doses associated with the therapy and/or malnutritional effects from intestinal drug application. The results should be corroborated by a larger longitudinal and controlled trial.

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CSF α-synuclein improves diagnostic and prognostic performance of CSF tau and Aβ in Alzheimer's disease

Acta Neuropathol. 2013 Jun 29. [Epub ahead of print]

Toledo JB, Korff A, Shaw LM, Trojanowski JQ, Zhang J.

Source

Department of Pathology and Laboratory Medicine, Institute on Aging, Center for Neurodegenerative Disease Research, University of Pennsylvania School of Medicine, Philadelphia, PA, USA.

Abstract

Alzheimer's disease (AD) and Lewy body diseases (LBD), e.g., Parkinson's disease (PD) dementia and dementia with Lewy bodies (DLB), are common causes of geriatric cognitive impairments. In addition, AD and LBD are often found in the same patients at autopsy; therefore, biomarkers that can detect the presence of both pathologies in living subjects are needed. In this investigation, we report the assessment of α-synuclein (α-syn) in cerebrospinal fluid (CSF) and its association with CSF total tau (t-tau), phosphorylated tau181 (p-tau181), and amyloid beta1-42 (Aβ1-42) in subjects of the Alzheimer's Disease Neuroimaging Initiative (ADNI; n = 389), with longitudinal clinical assessments. A strong correlation was noted between α-syn and t-tau in controls, as well as in patients with AD and mild cognitive impairment (MCI). However, the correlation is not specific to subjects in the ADNI cohort, as it was also seen in PD patients and controls enrolled in the Parkinson's Progression Markers Initiative (PPMI; n = 102). A bimodal distribution of CSF α-syn levels was observed in the ADNI cohort, with high levels of α-syn in the subjects with abnormally increased t-tau values. Although a correlation was also noted between α-syn and p-tau181, there was a mismatch (α-syn-p-tau181-Mis), i.e., higher p-tau181 levels accompanied by lower α-syn levels in a subset of ADNI patients. We hypothesize that this α-syn-p-tau181-Mis is a CSF signature of concomitant LBD pathology in AD patients. Hence, we suggest that inclusion of measures of CSF α-syn and calculation of α-syn-p-tau181-Mis improves the diagnostic sensitivity/specificity of classic CSF AD biomarkers and better predicts longitudinal cognitive changes.

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Genotype and phenotype in Parkinson's disease: Lessons in heterogeneity from deep brain stimulation.

Mov Disord. 2013 Jul 1. doi: 10.1002/mds.25535. [Epub ahead of print]

Angeli A, Mencacci NE, Duran R, Aviles-Olmos I, Kefalopoulou Z, Candelario J, Rusbridge S, Foley J, Pradhan P, Jahanshahi M, Zrinzo L, Hariz M, Wood NW, Hardy J, Limousin P, Foltynie T.

Source

Sobell Department of Motor Neuroscience, University College London (UCL) Institute of Neurology, Queen Square, London, United Kingdom.

Abstract

Variation in the genetic risk(s) of developing Parkinson's disease (PD) undoubtedly contributes to the subsequent phenotypic heterogeneity. Although patients with PD who undergo deep brain stimulation (DBS) are a skewed population, they represent a valuable resource for exploring the relationships between heterogeneous phenotypes and PD genetics. In this series, 94 patients who underwent DBS were screened for mutations in the most common genes associated with PD. The consequent genetic subgroups of patients were compared with respect to phenotype, levodopa (l-dopa), and DBS responsiveness. An unprecedented number (29%) of patients tested positive for at least 1 of the currently known PD genes. Patients with Parkin mutations presented at the youngest age but had many years of disease before needing DBS, whereas glucocerebrosidase (GBA) mutation carriers reached the threshold of needing DBS earlier, and developed earlier cognitive impairment after DBS. DBS cohorts include large numbers of gene positive PD patients and can be clinically instructive in the exploration of genotype-phenotype relationships.

© 2013 The Authors. Movement Disorders published by Wiley on behalf of The Movement Disorder Society.

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Clinical, genetic, and brain sonographic features related to Parkinson's disease in Gaucher disease

J Neurol. 2013 Jun 29. [Epub ahead of print]

Böttcher T, Rolfs A, Meyer B, Grossmann A, Berg D, Kropp P, Benecke R, Walter U.

Source

Albrecht-Kossel-Institute for Neuroregeneration, University of Rostock, Rostock, Germany.

Abstract

Homozygous or compound heterozygous mutations in the glucocerebrosidase gene cause Gaucher disease. Moreover, heterozygous glucocerebrosidase gene mutations represent the most common genetic risk factor for Parkinson's disease (PD) known so far. Substantia nigra (SN) hyperechogenicity, a sonographic feature thought to reflect iron accumulation, has been described in both PD and Gaucher disease patients. Here we studied how clinical, genetic, and brain sonographic findings relate to the occurrence of PD in Gaucher disease. Sixteen Gaucher disease patients, 12 PD patients, and 32 control subjects were enrolled. The glucocerebrosidase genotypes were identified by DNA sequencing. All subjects underwent transcranial ultrasound, and eight Gaucher disease patients additionally MRI for comparison with SN ultrasound findings. SN hyperechogenicity and reduced echogenicity of brainstem raphe were more frequent in Gaucher disease patients (62, 37 %) than in controls (12, 12 %; p < 0.001, p < 0.05). SN hyperechogenicity in Gaucher disease patients was unrelated to type or severity of glucocerebrosidase gene mutation, but correlated with iron-sensitive MRI-T2 hypointensity of SN pars compacta, and with age at start of enzyme replacement therapy. While none of the five Gaucher disease patients with signs of PD (definite PD, n = 4; early PD, n = 1) had severe glucocerebrosidase gene mutations known to cause neuronopathic Gaucher disease, all carried a N370S allele, previously reported to predict non-neuronopathic Gaucher disease. Hyposmia, higher non-motor symptoms score (constipation, depression, executive dysfunction), and SN hyperechogenicity were characteristic features of Gaucher disease-related PD. We conclude that the combined clinical, genetic, and transcranial sonographic assessment may improve the PD risk evaluation in Gaucher disease.

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Five-year fracture risk estimation in patients with Parkinson's disease

Bone. 2013 Jun 22. pii: S8756-3282(13)00236-6. doi: 10.1016/j.bone.2013.06.018. [Epub ahead of print]

Pouwels S, Bazelier MT, de Boer A, Weber WE, Neef CK, Cooper C, de Vries F.

Source

Utrecht Institute for Pharmaceutical Sciences, Universiteit Utrecht, Netherlands. Electronic address: s.pouwels@uu.nl.

Abstract

BACKGROUND:

Previous studies have shown that patients with Parkinson's Disease (PD) are at increased risk of fractures. However, no specific prediction model for fracture estimation among PD patients is currently available. Therefore, the aim of this study was to develop a simple score for estimating the 5-year osteoporotic and hip fracture risk among patients with PD.

METHODS:

The UK Clinical Practice Research Datalink (1987-2011) was used to identify incident PD patients. Cox proportional-hazards models were used to calculate the 5-year risk of osteoporotic and hip fracture among PD patients. The regression model was fitted with various risk factors for fracture and the final Cox model was converted into integer risk scores.

RESULTS:

We identified 4,411 incident PD patients without a history of osteoporotic treatment. The 5-year risks of osteoporotic and hip fracture were plotted in relation to the risk score. Risk scores increased with age, female gender, history of renal disease and history of dementia. The C-statistic, which is a parameter to test the internal validity of the model, was reasonable for the prediction of osteoporotic fracture (0.69) and hip fracture (0.73).

CONCLUSION:

In this study, we developed a simple model to estimate 5-year fracture risk among incident PD patients. It may be useful in daily practice after external validation.