Longitudinal midbrain changes in early Parkinson's disease: Iron content estimated from R2*/MRI

Parkinsonism Relat Disord. 2014 Nov 29. pii: S1353-8020(14)00452-0. doi: 10.1016/j.parkreldis.2014.11.017. [Epub ahead of print]

Wieler M, Gee M, Martin WR.

OBJECTIVE:

To determine whether, in patients with early Parkinson's disease (PD), longitudinal changes in midbrain iron content are associated with declining motor function over a period of three years.

METHODS:

Nineteen untreated subjects with early PD and 13 age- and sex-matched controls were followed clinically for 36 months. MRI with a 3 T magnet was performed at baseline, 18 months and 36 months with a multiple gradient echo sequence designed for rapid single-scan mapping of the proton transverse relaxation rate R2*. R2* was calculated for midbrain and forebrain basal ganglia regions.

RESULTS:

A difference in R2* between patients and controls was observed at baseline (p = 0.035) but not at 18 or 36 months in the lateral substantia nigra pars compacta (SNc). Linear regression indicated significant correlations between the change in R2* in the lateral SNc and the change score in UPDRS III (p = 0.008) and the PDQ-39 -mobility sub-score (p = 0.03) from baseline to 36 months. R2* tended to increase in those with more advanced disease and to decrease in those with milder disease.

CONCLUSIONS:

High field MRI demonstrates lateral SNc abnormalities that progress over 3 years in early PD consistent with increased iron content in those with more advanced disease, corresponding to the known distribution of neuronal loss occurring in this disorder, and correlating with motor symptomatology. Larger and longer investigations with more precise mapping of iron-containing midbrain structures are needed to fully evaluate the potential of R2* as a biomarker of disease progression in PD.

Substantia nigra neuromelanin magnetic resonance imaging in de novo Parkinson's disease patients

Another static imaging marker???...

Eur J Neurol. 2014 Dec 22. doi: 10.1111/ene.12613. [Epub ahead of print]

Reimão S, Pita Lobo P, Neutel D, Correia Guedes L, Coelho M, Rosa MM, Ferreira J, Abreu D, Gonçalves N, Morgado C, Nunes RG, Campos J, Ferreira JJ.

BACKGROUND:

Depigmentation of the substantia nigra (SN) and locus coeruleus (LC) is a conspicuous pathological feature of Parkinson's disease (PD) and is related to the loss of neuromelanin, whose paramagnetic properties result in high signal on specific T1-weighted magnetic resonance imaging (MRI). Recent studies have suggested that neuromelanin decrease in the SN and LC of PD patients may emerge as a possible diagnostic biomarker. The SN neuromelanin signal in de novo and early stage PD patients was studied to assess its diagnostic accuracy. This is the first study based on a semi-automated MRI analysis of the neuromelanin signal in de novo PD patients.

METHODS:

The inclusion criteria were untreated de novo PD and a 2-5 year disease duration; in addition, age matched healthy controls were enrolled. These were studied with a high-resolution T1-weighted MRI sequence at 3 T to visualize neuromelanin. The primary outcome was SN high signal area, length and neuromelanin/midbrain ratio obtained with semi-automated methods.

RESULTS:

A total of 12 de novo PD patients and 10 PD patients with a 2-5 year disease duration were evaluated. The area, length of the SN T1 high signal and the SN neuromelanin/midbrain ratio were markedly decreased in the PD groups compared with age-matched controls, with a substantial overlap between the two PD groups.

CONCLUSIONS:

Neuromelanin-sensitive MRI techniques can discriminate PD patients from healthy individuals with high sensitivity and specificity. Our findings are consistent with recent findings showing that PD neuromelanin changes remain stable during the course of the disease.

Diagnostic value of the REM sleep behavior disorder screening questionnaire in Parkinson's disease

Back-tracking perhaps... my impression is it is sensitive (particularly if one doesn't sleep alone) but there are a high number of false positives (i.e. low specificity)...

Sleep Med. 2014 Nov 13. pii: S1389-9457(14)00442-0. doi: 10.1016/j.sleep.2014.08.014. [Epub ahead of print]

Stiasny-Kolster K, Sixel-Döring F, Trenkwalder C, Heinzel-Gutenbrunner M, Seppi K, Poewe W, Högl B, Frauscher B.

OBJECTIVE:

We aimed to validate the rapid eye movement (REM) sleep behavior disorder (RBD) screening questionnaire (RBDSQ) in 2 independent samples of patients with Parkinson's disease (PD) using different settings when performing the investigations.

METHODS:

The RBDSQ was administered to two independent samples of 52 and 75 consecutive PD patients investigated with video-polysomnography (vPSG).

RESULTS:

In sample A, the RBDSQ identified 46/52 (88.5%) patients correctly. In sample B, 50/75 (66.7%) patients were identified correctly. Considering a cut-off score of ≥ 5 as a positive test result, sample A showed a sensitivity of 0.90 and a specificity of 0.87, sample B showed a sensitivity of 0.68 and a specificity of 0.63. Main differences between both groups were that patients of sample A underwent a sleep history including RBD assessment prior to administration of the RBDSQ, whereas in sample B the RBDSQ was administered during routine work-up.

CONCLUSIONS:

The diagnostic value of the RBDSQ strongly depends on the clinical setting and may be influenced by the individual's awareness on RBD. This finding is a critical issue which deserves clarification before use of this and other questionnaires can be recommended in epidemiological studies.

This study used a device worn as a belt to monitor the movement of people with and without PD as they slept. Individuals with PD moved less at night than healthy control participants. A group of healthy controls who were at 'high risk' of PD based on ultrasound imaging of the midbrain and subtle symptoms (slight motor signs and smell loss) did not differ in their levels of night-time movement from the lower-risk controls.

The fact that the group of 'high-risk' individuals did not have reduced night-time movement does not preculde the use of movement-tracking for early diagnosis of PD as the incidence of undiagnosed PD in this group may still have been too low to see a significant effect.

The DynaPort device used in the study:

Accelerometer-based quantitative analysis of axial nocturnal movements differentiates patients with Parkinson's disease, but not high-risk individuals, from controls 

J Neurol Neurosurg Psychiatry. 2015 Jan;86(1):32-7. doi: 10.1136/jnnp-2013-306851. Epub 2014 Apr 28

Abstract

Introduction There is a need for prodromal markers to diagnose Parkinson’s disease (PD) as early as possible. Knowing that most patients with overt PD have abnormal nocturnal movement patterns, we hypothesised that such changes might occur already in non-PD individuals with a potentially high risk for future development of the disease.

Methods Eleven patients with early PD (Hoehn & Yahr stage ≤2.5), 13 healthy controls and 33 subjects with a high risk of developing PD (HR-PD) were investigated. HR-PD was defined by the occurrence of hyperechogenicity of the substantia nigra in combination with prodromal markers (eg, slight motor signs, olfactory dysfunction). A triaxial accelerometer was used to quantify nocturnal movements during two nights per study participant. Outcome measurements included mean acceleration, and qualitative axial movement parameters, such as duration and speed.

Results Mean acceleration of nocturnal movements was lower in patients with PD compared to controls. Frequency and speed of axial movements did not differ between patients with PD and controls, but mean size and duration were lower in PD. The HR-PD group did not significantly differ from the control group in any of the parameters analysed.

Conclusions Compared with controls, patients with PD had an overall decreased mean acceleration, as well as smaller and shorter nocturnal axial movements. These changes did not occur in our potential HR-PD individuals, suggesting that relevant axial movement alterations during sleep have either not developed or cannot be detected by the means applied in this at-risk cohort.

PMID: 24777169

 

Authors: Louter M¹, Maetzler W², Prinzen J³, van Lummel RC³, Hobert M², Arends JB⁴, Bloem BR⁵, Streffer J⁶, Berg D², Overeem S¹, Liepelt-Scarfone I².

Author information

• ¹Department of Neurology, Donders Institute for Brain, Cognition and Behaviour, Radboud university medical centre, Nijmegen, The Netherlands Sleep Medicine Centre Kempenhaeghe, Heeze, The Netherlands.
• ²Department for Neurodegenerative Diseases, Centre of Neurology, German Center of Neurodegenerative Diseases and Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany.
• ³McRoberts, Den Haag, The Netherlands.
• ⁴Epilepsy Centre Kempenhaeghe, Heeze, The Netherlands Department of Electrical Engineering, University of Technology, Eindhoven, The Netherlands.
• ⁵Department of Neurology, Donders Institute for Brain, Cognition and Behaviour, Radboud university medical centre, Nijmegen, The Netherlands.
• ⁶Janssen Research and Development, Janssen-Pharmaceutical Companies of Johnson & Johnson, Beerse, Belgium.

 

Initial management of Parkinson's disease

Authoritative review in the BMJ...

http://www.bmj.com/content/349/bmj.g6258.long

BMJ. 2014 Dec 19;349:g6258. doi: 10.1136/bmj.g6258.

Goetz CG, Pal G.

Parkinson's disease is one of the most common neurodegenerative disorders seen in the United States and United Kingdom. The disease is characterised by two processes-cellular degeneration and the resulting biochemical deficiency of dopamine. Although these processes are inter-related, they are approached separately in the clinical setting. Currently, no proven neuroprotective or disease modifying treatment is available for Parkinson's disease. Several agents can be used to treat the motor symptoms associated with dopamine deficiency, and it is important to choose wisely when starting treatment. Drugs can have mild, moderate, or high potency, and the patient's goals, comorbidities, and the short and long term implications of choosing a specific agent should be taken into account when selecting the appropriate agent. Non-motor symptoms, such as depression, fatigue, and disorders of sleep and wakefulness, also need to be evaluated and treated. Research is under way to deliver dopaminergic therapy more effectively, but studies aimed at slowing or stopping disease progression have not shown promise.

Evolution of Prodromal Clinical Markers of Parkinson Disease in a GBA Mutation-Positive Cohort

Nice to see work describing more about the clinical features of non-PD GBA mutation carriers...

http://archneur.jamanetwork.com/article.aspx?articleid=2022386

JAMA Neurol. 2014 Dec 15. doi: 10.1001/jamaneurol.2014.2950. [Epub ahead of print]

Beavan M, McNeill A, Proukakis C, Hughes DA, Mehta A, Schapira AH.

IMPORTANCE:

Numerically, the most important genetic risk factor for the development of Parkinson disease (PD) is the presence of a glucocerebrosidase gene (GBA) mutation.

OBJECTIVE:

To evaluate longitudinally and clinically a GBA mutation-positive cohort and the evolution of the prodromal features of PD.

DESIGN, SETTING, AND PARTICIPANTS:

Participants in a study of the etiology and prodrome of PD were reevaluated in this clinic-based 2-year follow-up report. Patients with type 1 Gaucher disease (GD) and heterozygous GBA mutation carriers were recruited in 2010 from the Lysosomal Storage Disorder Unit at the Royal Free Hospital, London, England. Thirty patients who previously received a diagnosis of type 1 GD, 28 heterozygous GBA mutation carriers, and 26 genetically unrelated controls were included. Exclusion criteria included a diagnosis of PD or dementia for both the patients with GD and the GBA mutation carriers and any existing neurological disease for the controls.

MAIN OUTCOMES AND MEASURES:

Assessment was performed for clinical markers using standardized scales for hyposmia, rapid eye movement sleep behavior disorder, depression, autonomic dysfunction, cognitive function, and parkinsonian motor signs (using the Unified Parkinson's Disease Rating Scale motor subscale [UPDRS part III]).

RESULTS:

Over 2 years, depression scores were significantly worse for heterozygous carriers (mean baseline, 0.65; mean follow-up, 2.88; P = .01), rapid eye movement sleep behavior disorder scores were significantly worse for patients with GD (mean baseline, 0.93; mean follow-up, 2.93; P < .001) and heterozygotes (mean baseline, 0.10; mean follow-up, 2.30; P < .001), and UPDRS part III scores were significantly worse for patients with GD (mean baseline, 4.29; mean follow-up, 7.82; P < .001) and heterozygotes (mean baseline, 1.97; mean follow-up, 4.50; P < .001). For controls, there was a small but significant deterioration in the UPDRS part II (activities of daily living) score (mean baseline, 0.00; mean follow-up, 0.58; P = .006). At 2 years, olfactory and cognitive assessment scores were lower in patients with GD and heterozygotes compared with controls, but they did not differ significantly from baseline. When the results from the patients with GD and the heterozygotes were combined, a significant deterioration from baseline was observed, as reflected in the Rapid Eye Movement Sleep Behaviour Disorder Questionnaire (mean baseline, 0.51; mean follow-up, 2.63; P < .001), Beck Depression Inventory (mean baseline, 1.72; mean follow-up, 4.44; P = .002), and UPDRS part II (mean baseline, 0.88; mean follow-up, 2.01; P < .001) and part III scores (mean baseline, 3.09; mean follow-up, 6.10; P < .001) (all P < .01), and at 2 years, significant differences in University of Pennsylvania Smell Identification Test, Unified Multiple System Atrophy Rating Scale, Mini-Mental State Examination, Montreal Cognitive Assessment, and UPDRS part II and part III scores were observed between patients with GD/heterozygotes and controls (all P < .05).

CONCLUSIONS AND RELEVANCE:

This study indicates that, as a group, GBA mutation-positive individuals show a deterioration in clinical markers consistent with the prodrome of PD. Within this group of individual, 10% appear to be evolving at a more rapid rate.

Priority setting partnership to identify the top 10 research priorities for the management of Parkinson's disease

Top 10 research priorities for Parkinson's...

http://bmjopen.bmj.com/content/4/12/e006434.long

BMJ Open. 2014 Dec 14;4(12):e006434. doi: 10.1136/bmjopen-2014-006434.

Deane KH, Flaherty H, Daley DJ, Pascoe R, Penhale B, Clarke CE, Sackley C, Storey S.

OBJECTIVES:

This priority setting partnership was commissioned by Parkinson's UK to encourage people with direct and personal experience of the condition to work together to identify and prioritise the top 10 evidential uncertainties that impact on everyday clinical practice for the management of Parkinson's disease (PD).

SETTING:

The UK.

PARTICIPANTS:

Anyone with experience of PD including: people with Parkinson's (PwP), carers, family and friends, healthcare and social care professionals. Non-clinical researchers and employees of pharmaceutical or medical devices companies were excluded. 1000 participants (60% PwP) provided ideas on research uncertainties, 475 (72% PwP) initially prioritised them and 27 (37% PwP) stakeholders agreed a final top 10.

METHODS:

Using a modified nominal group technique, participants were surveyed to identify what issues for the management of PD needed research. Unique research questions unanswered by current evidence were identified and participants were asked to identify their top 10 research priorities from this list. The top 26 uncertainties were presented to a consensus meeting with key stakeholders to agree the top 10 research priorities.

RESULTS:

1000 participants provided 4100 responses, which contained 94 unique unanswered research questions that were initially prioritised by 475 participants. A consensus meeting with 27 stakeholders agreed the top 10 research priorities. The overarching research aspiration was an effective cure for PD. The top 10 research priorities for PD management included the need to address motor symptoms (balance and falls, and fine motor control), non-motor symptoms (sleep and urinary dysfunction), mental health issues (stress and anxiety, dementia and mild cognitive impairments), side effects of medications (dyskinesia) and the need to develop interventions specific to the phenotypes of PD and better monitoring methods.

CONCLUSIONS:

These research priorities identify crucial gaps in the existing evidence to address everyday practicalities in the management of the complexities of PD.

Mutations in the glucocerebrosidase gene are responsible for Chinese patients with Parkinson's disease

J Hum Genet. 2014 Dec 18. doi: 10.1038/jhg.2014.110. [Epub ahead of print]

Yu Z, Wang T, Xu J, Wang W, Wang G, Chen C, Zheng L, Pan L, Gong D, Li X, Qu H, Li F, Zhang B, Le W, Han F.

Abstract

Pathological mutations in the glucocerebrosidase gene (GBA) have been suggested to be associated with Parkinson's disease (PD) in various ethnic populations. Most studies on Chinese PD patients have only screened the N370S and L444P mutations in the GBA gene. To investigate the GBA mutations in Chinese population, we performed complete sequencing of the GBA gene in 184 Chinese PD patients and 130 Chinese control individuals. As a result, we identified three novel and nine reported GBA mutations. The novel mutations include 5-bp deletion (c.334_338delCAGAA), L264I and L314V and the nine reported GBA mutations are R163Q, F213I, E326K, S364S, F347L, V375L, L444P, RecNciI and Q497R. The novel 5-bp deletion (CAGAA) produces a short truncated GBA protein of 142 amino acids, which loses major function domains of the 536 amino acids. Our data also reveals that the frequency of GBA mutations within this Chinese PD cohort was 8.7%, which is significantly higher than 1.54% observed in the Chinese control cohort (χ2=7.22, P=0.0072; odds ratio (OR)=6.095, 95% confidence interval of OR=1.546-24.030). The most common L444P mutation accounts 2.74%, which confer more genetic risk for PD in this Chinese population. In conclusion, novel and known GBA mutations were identified and were found to be associated to PD in this Chinese population

Reasons for mild parkinsonian signs - Which constellation may indicate neurodegeneration?

http://www.sciencedirect.com/science/article/pii/S1353802014004532

Parkinsonism Relat Disord. 2014 Nov 28. pii: S1353-8020(14)00453-2. doi: 10.1016/j.parkreldis.2014.11.018. [Epub ahead of print]

Lerche S, Brockmann K, Wurster I, Gaenslen A, Roeben B, Holz D, Eschweiler GW, Maetzler W, Berg D.

INTRODUCTION:

Mild parkinsonian signs (MPS) are common in the elderly population. Several factors including physical decline and comorbidities in addition to neurodegeneration may be possible sources for MPS. The objective was to examine whether MPS are associated with a history of orthopedic disturbances, vascular diseases or prodromal markers for neurodegeneration.

METHODS:

The TREND study is a prospective longitudinal cohort study in individuals >50 years with biennial assessments designed to identify prodromal markers for neurodegeneration. In this substudy, 1091 elderly individuals were evaluated for a possible association of MPS with prodromal markers for neurodegeneration, orthopedic disturbances, vascular diseases, as well as cerebral abnormalities. These factors were assessed by self-administered questionnaires, with a structured health interview, a neurological examination and by transcranial sonography.

RESULTS:

82 participants showed MPS. They were found to have more often hyposmia and RBD, had a higher autonomic dysfunction score and they more frequently showed hyperechogenicity of the substantia nigra compared to controls. Neither orthopedic disturbances nor vascular diseases were significantly associated with the prevalence of MPS.

CONCLUSION:

MPS might be a sign of early neurodegeneration rather than caused by other motor influencing diseases.

Distinguishing idiopathic Parkinson's disease from other parkinsonian syndromes by breath test

http://www.sciencedirect.com/science/article/pii/S1353802014004581

Parkinsonism Relat Disord. 2014 Dec 9. pii: S1353-8020(14)00458-1. doi: 10.1016/j.parkreldis.2014.11.023. [Epub ahead of print]

Nakhleh MK, Badarny S, Winer R, Jeries R, Finberg J, Haick H.

INTRODUCTION:

Diagnosis of different parkinsonian syndromes is linked with high misdiagnosis rates and various confounding factors. This is particularly problematic in its early stages. With this in mind, the current pilot study aimed to distinguish between Idiopathic Parkinson's Disease (iPD), other Parkinsonian syndromes (non-iPD) and healthy subjects, by a breath test that analyzes the exhaled volatile organic compounds using a highly sensitive nanoarray.

METHODS:

Breath samples of 44 iPD, 16 non-iPD patients and 37 healthy controls were collected. The samples were passed over a nanoarray and the resulting electrical signals were analyzed with discriminant factor analysis as well as by a K-fold cross-validation method, to test the accuracy of the model.

RESULTS:

Comparison of non-iPD with iPD states yielded 88% sensitivity, 88% accuracy, and 88% Receiver Operating Characteristic area under the curve in the training set samples with known identity. The validation set of this comparison scored 81% sensitivity and accuracy and 92% negative predictive value. Comparison between atypical parkinsonism states and healthy subjects scored 94% sensitivity and 85% accuracy in the training set samples with known identity. The validation set of this comparison scored 81% sensitivity and 78% accuracy. The obtained results were not affected by l-Dopa or MAO-B inhibitor treatment.

CONCLUSIONS:

Exhaled breath analysis with nanoarray is a promising approach for a non-invasive, inexpensive, and portable technique for differentiation between different Parkinsonian states. A larger cohort is required in order to establish the clinical usefulness of the method.

Cerebrospinal fluid biomarkers in trials for Alzheimer and Parkinson diseases

http://www.nature.com/nrneurol/journal/vaop/ncurrent/full/nrneurol.2014.232.html

Nat Rev Neurol. 2014 Dec 16. doi: 10.1038/nrneurol.2014.232. [Epub ahead of print]

Lleó A, Cavedo E, Parnetti L, Vanderstichele H, Herukka SK, Andreasen N, Ghidoni R, Lewczuk P, Jeromin A, Winblad B, Tsolaki M, Mroczko B, Visser PJ, Santana I, Svenningsson P, Blennow K, Aarsland D, Molinuevo JL, Zetterberg H, Mollenhauer B.

Alzheimer disease (AD) and Parkinson disease (PD) are the most common neurodegenerative disorders. For both diseases, early intervention is thought to be essential to the success of disease-modifying treatments. Cerebrospinal fluid (CSF) can reflect some of the pathophysiological changes that occur in the brain, and the number of CSF biomarkers under investigation in neurodegenerative conditions has grown rapidly in the past 20 years. In AD, CSF biomarkers are increasingly being used in clinical practice, and have been incorporated into the majority of clinical trials to demonstrate target engagement, to enrich or stratify patient groups, and to find evidence of disease modification. In PD, CSF biomarkers have not yet reached the clinic, but are being studied in patients with parkinsonism, and are being used in clinical trials either to monitor progression or to demonstrate target engagement and downstream effects of drugs. CSF biomarkers might also serve as surrogate markers of clinical benefit after a specific therapeutic intervention, although additional data are required. It is anticipated that CSF biomarkers will have an important role in trials aimed at disease modification in the near future. In this Review, we provide an overview of CSF biomarkers in AD and PD, and discuss their role in clinical trials.