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.

Sick individuals and sick populations

A classic...

http://ije.oxfordjournals.org/content/14/1/32.long

Int J Epidemiol. 1985 Mar;14(1):32-8.

Rose G.

Abstract

Aetiology confronts two distinct issues: the determinants of individual cases, and the determinants of incidence rate. If exposure to a necessary agent is homogeneous within a population, then case/control and cohort methods will fail to detect it: they will only identify markers of susceptibility. The corresponding strategies in control are the 'high-risk' approach, which seeks to protect susceptible individuals, and the population approach, which seeks to control the causes of incidence. The two approaches are not usually in competition, but the prior concern should always be to discover and control the causes of incidence.

The clinical characteristics of dementia with Lewy bodies and a consideration of prodromal diagnosis

PREDICT-DLB???...

http://alzres.com/content/6/4/46

Alzheimers Res Ther. 2014 Jul 21;6(4):46. eCollection 2014.

Donaghy PC, McKeith IG.

Abstract

Dementia with Lewy bodies (DLB) is the second most common type of degenerative dementia following Alzheimer's disease (AD). DLB is clinically and pathologically related to Parkinson's disease (PD) and PD dementia, and the three disorders can be viewed as existing on a spectrum of Lewy body disease. In recent years there has been a concerted effort to establish the phenotypes of AD and PD in the prodromal phase (before the respective syndromes of cognitive and motor impairment are expressed). Evidence for the prodromal presentation of DLB is also emerging. This paper briefly reviews what is known about the clinical presentation of prodromal DLB before discussing the pathology of Lewy body disease and how this relates to potential biomarkers of prodromal DLB. The presenting features of DLB can be broadly placed in three categories: cognitive impairment (particularly nonamnestic cognitive impairments), behavioural/psychiatric phenomena (for example, hallucinations, rapid eye movement sleep behaviour disorder (RBD)) and physical symptoms (for example, parkinsonism, decreased sense of smell, autonomic dysfunction). Some noncognitive symptoms such as constipation, RBD, hyposmia and postural dizziness can predate the onset of memory impairment by several years in DLB. Pathological studies of Lewy body disease have found that the earliest sites of involvement are the olfactory bulb, the dorsal motor nucleus of the vagal nerve, the peripheral autonomic nervous system, including the enteric nervous system, and the brainstem. Some of the most promising early markers for DLB include the presence of RBD, autonomic dysfunction or hyposmia, 123I-metaiodobenzylguanidine cardiac scintigraphy, measures of substantia nigra pathology and skin biopsy for α-synuclein in peripheral autonomic nerves. In the absence of disease-modifying therapies, the diagnosis of prodromal DLB is of limited use in the clinic. That said, knowledge of the prodromal development of DLB could help clinicians identify cases of DLB where the diagnosis is uncertain. Prodromal diagnosis is of great importance in research, where identifying Lewy body disease at an earlier stage may allow researchers to investigate the initial phases of dementia pathophysiology, develop treatments designed to interrupt the development of the dementia syndrome and accurately identify the patients most likely to benefit from these treatments.

Dopamine transporter imaging as a diagnostic tool for parkinsonism and related disorders in clinical practice

Parkinsonism Relat Disord. 2014 Nov 20. pii: S1353-8020(14)00420-9. doi: 10.1016/j.parkreldis.2014.11.007. [Epub ahead of print]

Ba F, Martin WR.

BACKGROUND:

Accurate diagnosis of Parkinson disease (PD) and other degenerative parkinsonian syndromes is important for management and prognostic purposes. Diagnosis can be challenging in early disease and in atypical cases.

METHODS:

We reviewed the literature on the application of dopamine transporter single-photon emission computed tomography (DAT-SPECT) in degenerative parkinsonism and related disorders as a diagnostic tool.

RESULTS:

The use of DAT-SPECT shows some utility in the early diagnosis of PD and differentiation from other non-degenerative parkinsonian disorders (i.e. essential tremor, dystonic tremor, drug-induced and in most cases of psychogenic parkinsonism), since it can accurately detect the presynaptic dopaminergic deficit. The test has been shown to have high sensitivity/specificity by multiple studies. DAT imaging may also have some prognostic value for disease progression. However, it has limited value in differentiating among degenerative causes of parkinsonism. DAT imaging has some limitations. In most studies, true test accuracy is unknown since the gold standard is clinical diagnosis by a movement disorders neurologist. Therefore, the sensitivity of the test cannot exceed that of the clinical diagnosis. In addition, false negative scans occur and highlight the need for clinical follow-up.

CONCLUSION:

Clinical assessment remains the most important aspect in evaluating these patients. DAT-SPECT is a sensitive modality to detect nigrostriatal degeneration. In spite of increasing data using this technique, however, more long-term clinical studies are required to determine how DAT-SPECT scan can guide decision-making.