Wednesday, 31 December 2014
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
Tuesday, 30 December 2014
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.
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.
The RBDSQ was administered to two independent samples of 52 and 75 consecutive PD patients investigated with video-polysomnography (vPSG).
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.
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.
Sunday, 28 December 2014
Accelerometer-based quantitative analysis of axial nocturnal movements differentiates patients with Parkinson's disease, but not high-risk individuals, from controls
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
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.
- 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.
Tuesday, 23 December 2014
Authoritative review in the BMJ...
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.
Monday, 22 December 2014
Nice to see work describing more about the clinical features of non-PD GBA mutation carriers...
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.
Numerically, the most important genetic risk factor for the development of Parkinson disease (PD) is the presence of a glucocerebrosidase gene (GBA) mutation.
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]).
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.
Sunday, 21 December 2014
Priority setting partnership to identify the top 10 research priorities for the management of Parkinson's disease
Top 10 research priorities for Parkinson's...
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.
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).
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.
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.
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.
These research priorities identify crucial gaps in the existing evidence to address everyday practicalities in the management of the complexities of PD.
Saturday, 20 December 2014
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.
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
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.
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.
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.
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.
MPS might be a sign of early neurodegeneration rather than caused by other motor influencing diseases.
Friday, 19 December 2014
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.
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.
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.
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.
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.
Thursday, 18 December 2014
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.
Wednesday, 17 December 2014
Int J Epidemiol. 1985 Mar;14(1):32-8.
Saturday, 13 December 2014
The clinical characteristics of dementia with Lewy bodies and a consideration of prodromal diagnosis
Alzheimers Res Ther. 2014 Jul 21;6(4):46. eCollection 2014.
Donaghy PC, McKeith IG.
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.
Friday, 12 December 2014
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.
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.
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.
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.
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.
Thursday, 11 December 2014
Four pioneers of L-dopa treatment: Arvid Carlsson, Oleh Hornykiewicz, George Cotzias, and Melvin Yahr
Great to learn more about the people behind what remains our best drug...
Mov Disord. 2014 Dec 8. doi: 10.1002/mds.26120. [Epub ahead of print]
Lees AJ, Tolosa E, Olanow CW.
Four individuals stand out as pioneers of the early work that led to levodopa becoming a revolutionary new treatment for Parkinson's disease: Arvid Carlsson, Oleh Hornykiewicz, George C. Cotzias, and Melvin D. Yahr. All four were MDs. The first three had extra training in pharmacology, and in fact did their research in pharmacology. The fourth was a clinical neurologist, the only one in this group with those credentials. The story starts with Carlsson, who became interested in studying the mechanism of reserpine's sedative effect, now recognized as a drug-induced parkinsonian state. A key experiment in 1957 showed that levodopa (l-dopa) could alleviate the immobility induced by reserpine in animals. Carlsson then showed that reserpine depleted brain dopamine, and that l-dopa restored it. Carlsson developed a sensitive fluorescent technique to measure dopamine levels, and his laboratory also showed the distribution of dopamine in animal brain to be highest in the striatum. Within a year, Carlsson postulated that dopamine appears to play a role in motor function. His proposal that dopamine serves as a neurotransmitter in brain was met with much skepticism, but he persisted and continued to study brain dopamine, eventually leading to being awarded the Nobel Prize in Medicine in 2000. Hornykiewicz also went into pharmacology research after graduating from medical school. Fortuitously, his assigned first project was on the blood pressure effects of dopamine, recognized as a precursor of norepinephrine. When he completed his postdoctoral studies, Carlsson's work on the reserpinized animal and on the regional distribution of brain dopamine was published. This inspired Hornykiewicz to determine dopamine levels in patients with Parkinson's disease. He obtained postmortem material, and his 1960 paper showed a marked depletion of dopamine in the striatum in this disorder. He went on in subsequent papers to correlate severity of parkinsonian features with the amount of striatal dopamine depletion. In the meantime, after his discovery of low dopamine in brains of patients with Parkinson's disease, Hornykiewicz persuaded Walther Birkmayer to inject l-dopa into patients. They reported success and continued this treatment, usually combining it with the use of a monoamine oxidase inhibitor. However, the response was limited in duration, and subsequent trials by others were not achieving similar success, and many failed to find any benefit. The fulfilment of the l-dopa story stemmed from the hypothesis held by Cotzias that Parkinson's disease was caused by loss of brain neuromelanin in the substantia nigra. Although Cotzias's research had been in pharmacology, he also headed a clinical pharmacology research group at a federal laboratory on Long Island, New York, USA. He decided to try to restore this pigment in patients, not animals, and one of the three drugs he tried was d,l-dopa. As reported in his 1967 article, d,l-dopa proved to be dramatically successful in reversing the symptoms, but at extremely high dosages and with considerable hematologic adverse effects. Cotzias immediately tested l-dopa and found the same benefit with half the dosage and without the hematologic problems. Yahr was a clinical neurologist who had been treating patients with PD with available therapy and also headed a federally financed research group investigating the disorder. Always on the lookout for potential new treatments, he was initially skeptical about l-dopa when studies with low doses were being reported. Seeing videos of patients presented by Cotzias, however, he realized that the results needed confirmation through a double-blind controlled clinical trial. He proceeded to develop and execute such a trial with l-dopa, duplicating Cotzias's success. Both Cotzias and Yahr had encountered motor fluctuations and dyskinesias, but the amelioration of bradykinesia, rigidity, and tremor was so pronounced that these adverse effects did not prevent regulatory approval of l-dopa, and almost 50 years later l-dopa remains the most effective pharmacologic agent for treating Parkinson's disease. This article relates the personal stories of these four pioneers and how they achieved their success.
Tuesday, 9 December 2014
Identification of candidate genes for Parkinson's disease through blood transcriptome analysis in LRRK2-G2019S carriers, idiopathic cases, and controls
Neurobiol Aging. 2014 Nov 5. pii: S0197-4580(14)00705-2. doi: 10.1016/j.neurobiolaging.2014.10.039. [Epub ahead of print]
Infante J, Prieto C, Sierra M, Sánchez-Juan P, González-Aramburu I, Sánchez-Quintana C, Berciano J, Combarros O, Sainz J.
The commonest known cause of Parkinson's disease (PD) is the G2019S mutation of the LRRK2 gene, but this mutation is not sufficient for causing PD, and many carriers of the mutation never develop PD symptoms during life. Differences at the expression level of certain genes, resulting from either genetic variations or environmental interactions, might be one of the mechanisms underlying differential risks for developing both idiopathic and genetic PD. To identify the genes involved in PD pathogenesis, we compared genome-wide gene expression (RNA-seq) in peripheral blood of 20 PD patients carrying the G2019S mutation of the LRRK2 gene, 20 asymptomatic carriers of the mutation, 20 subjects with idiopathic PD, 20 controls and 7 PD patients before and after initiating dopaminergic therapy. We identified 13 common genes (ADARB2, CEACAM6, CNTNAP2, COL19A1, DEF4, DRAXIN, FCER2, HBG1, NCAPG2, PVRL2, SLC2A14, SNCA, and TCL1B) showing significant differential expression between G2019S-associated PD and asymptomatic carriers and also between idiopathic PD and controls but not between untreated and treated patients. Some of these genes are functionally involved in the processes known to be involved in PD pathogenesis, such as Akt signaling, glucose metabolism, or immunity. We consider that these genes merit further attention in future studies as potential candidate genes involved in both idiopathic and LRRK2-G2019S-associated forms of PD.
Monday, 8 December 2014
Mov Disord. 2014 Dec 1. doi: 10.1002/mds.26077. [Epub ahead of print]
Pont-Sunyer C, Hotter A, Gaig C, Seppi K, Compta Y, Katzenschlager R, Mas N, Hofeneder D, Brücke T, Bayés A, Wenzel K, Infante J, Zach H, Pirker W, Posada IJ, Alvarez R, Ispierto L, De Fàbregues O, Callén A, Palasí A, Aguilar M, Martí MJ, Valldeoriola F, Salamero M, Poewe W, Tolosa E.
Nonmotor symptoms (NMS) in Parkinson's disease (PD) can precede onset of motor symptoms. Relationship between premotor symptoms onset and motor features is limited. Our aim is to describe the presence and perceived onset of NMS in PD as well as their possible association with motor phenotype. Presence and onset of NMS were assessed by a custom-made questionnaire in 109 newly diagnosed untreated PD patients and 107 controls from 11 Spanish and Austrian centers. Seventeen of thirty-one NMS were more common in patients than controls (P < 0.05). They were usually mild and frequently reported to occur at different time-spans before motor symptoms. Anhedonia, apathy, memory complaints, and inattention occurred more frequently during the 2-year premotor period. Those reported more frequently in the 2- to 10-year premotor period were smell loss, mood disturbances, taste loss, excessive sweating, fatigue, and pain. Constipation, dream-enacting behavior, excessive daytime sleepiness, and postprandial fullness were frequently perceived more than 10 years before motor symptoms. No correlation between NMS burden and motor severity, age, or gender was observed. NMS associated in four clusters: rapid eye movement sleep behavior disorder symptoms-constipation, cognition-related, mood-related, and sensory clusters. No cluster was associated with a specific motor phenotype or severity. NMS are common in early unmedicated PD and frequently reported to occur in the premotor period. They are generally mild, but a patient subgroup showed high NMS burden mainly resulting from cognition-related symptoms. Certain NMS when present at the time of assessment or in the premotor stage, either alone or in combination, allowed discriminating PD from controls.
Sunday, 7 December 2014
A different and interesting take on the gut and Parkinson's...
Mov Disord. 2014 Dec 5. doi: 10.1002/mds.26069. [Epub ahead of print]
Scheperjans F, Aho V, Pereira PA, Koskinen K, Paulin L, Pekkonen E, Haapaniemi E, Kaakkola S, Eerola-Rautio J, Pohja M, Kinnunen E, Murros K, Auvinen P.
In the course of Parkinson's disease (PD), the enteric nervous system (ENS) and parasympathetic nerves are amongst the structures earliest and most frequently affected by alpha-synuclein pathology. Accordingly, gastrointestinal dysfunction, in particular constipation, is an important non-motor symptom in PD and often precedes the onset of motor symptoms by years. Recent research has shown that intestinal microbiota interact with the autonomic and central nervous system via diverse pathways including the ENS and vagal nerve. The gut microbiome in PD has not been previously investigated. We compared the fecal microbiomes of 72 PD patients and 72 control subjects by pyrosequencing the V1-V3 regions of the bacterial 16S ribosomal RNA gene. Associations between clinical parameters and microbiota were analyzed using generalized linear models, taking into account potential confounders. On average, the abundance of Prevotellaceae in feces of PD patients was reduced by 77.6% as compared with controls. Relative abundance of Prevotellaceae of 6.5% or less had 86.1% sensitivity and 38.9% specificity for PD. A logistic regression classifier based on the abundance of four bacterial families and the severity of constipation identified PD patients with 66.7% sensitivity and 90.3% specificity. The relative abundance of Enterobacteriaceae was positively associated with the severity of postural instability and gait difficulty. These findings suggest that the intestinal microbiome is altered in PD and is related to motor phenotype. Further studies are warranted to elucidate the temporal and causal relationships between gut microbiota and PD and the suitability of the microbiome as a biomarker.
Neuroscience. 2014 Oct 22. pii: S0306-4522(14)00892-6. doi: 10.1016/j.neuroscience.2014.10.028. [Epub ahead of print]
Dzamko N, Geczy CL, Halliday GM.
Inflammation has long been associated with the pathogenesis of Parkinson's disease (PD) but the extent to which it is a cause or consequence is sill debated. Over the past decade a number of genes have been implicated in PD. Relatively rare missense mutations in genes such as LRRK2, Parkin, SNCA and PINK1 are causative for familial PD whereas more common variation in genes, including LRRK2, SNCA and GBA, comprise risk factors for sporadic PD. Determining how the function of these genes and the proteins they encode are altered in PD has become a priority, as results will likely provide much needed insights into contributing causes. Accumulating evidence indicates that many of these genes function in pathways that regulate aspects of immunity, particularly inflammation, suggesting close associations between PD and immune homeostasis.
Saturday, 6 December 2014
Clinical characteristics related to worsening of motor function assessed by the Unified Parkinson's Disease Rating Scale in the elderly population
J Neurol. 2014 Dec 2. [Epub ahead of print]
Liepelt-Scarfone I, Lerche S, Behnke S, Godau J, Gaenslen A, Pausch C, Fassbender K, Brockmann K, Srulijes K, Huber H, Wurster I, Berg D.
There is evidence that nigrostriatal pathology may at least partly underlie mild Parkinsonian signs. We evaluated whether an increase in the Unified Parkinson's Disease Rating Scale part III (UPDRS-III) could be predicted by the presence of risk and prodromal markers for neurodegenerative diseases in elderly individuals without those diseases. Therefore, we analyzed the UPDRS-III score and various risk and prodromal markers known to antecede neurodegenerative diseases in a population-based cohort comprising 807 individuals free of neurodegenerative diseases at baseline. After 5 years, eight persons (1.0 %) were diagnosed with Parkinson's Disease (PD). Of those, seven (87.5 %) had motor worsening ≥3 points on the UPDRS-III from baseline to follow-up, one had two points increase. Of the 788 people without PD, 568 (72.1 %) showed no increase in the UPDRS-III scale, 220 (27.9 %) had ≥1 point increase and out of these 104 (13.2 %) had an increase of ≥3 points in the UPDRS-III score after 5 years. We identified an age >60 years (relative risk, RR = 1.7; confidence interval, CI 1.3-2.1) and the occurrence of ≥2 risk factors (RR = 1.5; CI 1.2-1.9) as possible predictors of motor progression. After 5 years, individuals with an increase in the UPDRS-III score had more often a one-sided reduced arm swing (p < 0.001) and identified less odors in the Sniffin' sticks test (p < 0.041) than persons with stable motor performance. Our data support the assumption that progression of Parkinsonian signs assessed by the UPDRS-III parallels the development of prodromal markers for neurodegenerative diseases in the elderly population.
Friday, 5 December 2014
Clin Neurol Neurosurg. 2014 Dec;127:71-4. doi: 10.1016/j.clineuro.2014.09.014. Epub 2014 Oct 5.
Munhoz RP, Teive HA.
REM sleep behaviour disorder (RBD) is typically linked to synucleinopathies (SP). In this study we analyzed the utility and performance of RBD as a tool for the differential diagnosis of the most common forms of degenerative parkinsonism, including SPs and tauopathies.
Patients with a syndromic diagnosis of degenerative parkinsonism matched for gender, age, and disease stage were assessed using a structured protocol with demographic and clinical data, including the diagnosis of probable RBD (pRBD), ascertained clinically using established criteria.
One hundred cases of Parkinson's disease (PD), 87 with progressive supranuclear palsy (PSP), 72 with the parkinsonian form of multiple system atrophy (MSA), 50 with dementia with Lewy bodies (DLB), and 18 with corticobasal degeneration (CBD) were included. pRBD was found in 58 (58%) of the PD patients, 59 (81.9%) of those with MSA, 37 (74%) with DLB, 32 (36.7%) with PSP, and one (5.5%) with CBD. Among the SPs, pRBD was significantly more common in MSA when compared with PD patients. Differences were also significant individually for all SPs when compared to PSP. The positive predictive value (PPV) of pRBD for a SP was 82.3%, but sensitivity was 69.4% and specificity 68.6%.
In our sample, pRBD was more frequent in SPs than in PSP and CBD, however, its' frequency in PSP was significant. Although pRBD had a good PPV for a SP, all other measurements used for determine diagnostic performance were disappointing.
Thursday, 4 December 2014
And of course if the aim in to detect at-risk or prodromal PD, then this goes hand-in-hand...
Nat Rev Neurol. 2014 Dec 2. doi: 10.1038/nrneurol.2014.226. [Epub ahead of print]
Athauda D, Foltynie T.
Many agents developed for neuroprotective treatment of Parkinson disease (PD) have shown great promise in the laboratory, but none have translated to positive results in patients with PD. Potential neuroprotective drugs, such as ubiquinone, creatine and PYM50028, have failed to show any clinical benefits in recent high-profile clinical trials. This 'failure to translate' is likely to be related primarily to our incomplete understanding of the pathogenic mechanisms underlying PD, and excessive reliance on data from toxin-based animal models to judge which agents should be selected for clinical trials. Restricted resources inevitably mean that difficult compromises must be made in terms of trial design, and reliable estimation of efficacy is further hampered by the absence of validated biomarkers of disease progression. Drug development in PD dementia has been mostly unsuccessful; however, emerging biochemical, genetic and pathological evidence suggests a link between tau and amyloid-β deposition and cognitive decline in PD, potentially opening up new possibilities for therapeutic intervention. This Review discusses the most important 'druggable' disease mechanisms in PD, as well as the most-promising drugs that are being evaluated for their potential efficiency in treatment of motor and cognitive impairments in PD.
Great to have been involved in this study. It is amazing the see the symptoms and relative incidence of early features preceding diagnosis, played out in single cohort...
Lancet Neurol. 2014 Nov 26. pii: S1474-4422(14)70287-X. doi: 10.1016/S1474-4422(14)70287-X. [Epub ahead of print]
Schrag A, Horsfall L, Walters K, Noyce A, Petersen I.
Parkinson's disease has an insidious onset and is diagnosed when typical motor features occur. Several motor and non-motor features can occur before diagnosis, early in the disease process. We aimed to assess the association between first presentation of several prediagnostic features in primary care and a subsequent diagnosis of Parkinson's disease, and to chart the timeline of these first presentations before diagnosis.
We identified individuals with a first diagnosis of Parkinson's disease and those without Parkinson's disease from Jan 1, 1996, to Dec 31, 2012, from The Health Improvement Network UK primary care database. Codes were extracted for a range of possible prediagnostic or early symptoms, comprising motor features (tremor, rigidity, balance impairments, neck pain or stiffness, and shoulder pain or stiffness), autonomic features (constipation, hypotension, erectile dysfunction, urinary dysfunction, and dizziness), neuropsychiatric disturbances (memory problems, late-onset anxiety or depression, cognitive decline, and apathy), and additional features (fatigue, insomnia, anosmia, hypersalivation and rapid-eye-movement sleep behaviour disorder) in the years before diagnosis. We report the incidence of symptoms recorded in more than 1% of cases per 1000 person-years and incidence risk ratios (RRs) for individuals with and without Parkinson's disease at 2, 5, and 10 years before diagnosis.
8166 individuals with and 46 755 individuals without Parkinson's disease were included in the study. Apathy, REM sleep behaviour disorder, anosmia, hypersalivation, and cognitive decline were all reported in less than 1% of people per 1000 person-years and were excluded from further analyses. At 2 years before Parkinson's disease diagnosis, the incidence of all studied prediagnostic features except neck pain or stiffness was higher in patients who went on to develop Parkinson's disease (n=7232) than in controls (n=40 541). At 5 years before diagnosis, compared with controls (n=25 544), patients who went on to develop Parkinson's disease (n=4769) had a higher incidence of tremor (RR 13·70, 95% CI 7·82-24·31), balance impairments (2·19, 1·09-4·16), constipation (2·24, 2·04-2·46), hypotension (3·23, 1·85-5·52), erectile dysfunction (1·30, 1·11-1·51), urinary dysfunction (1·96, 1·34-2·80), dizziness (1·99, 1·67-2·37), fatigue (1·56, 1·27-1·91), depression (1·76, 1·41-2·17), and anxiety (1·41, 1·09-1·79). At 10 years before diagnosis of Parkinson's disease, the incidence of tremor (RR 7·59, 95% CI 1·11-44·83) and constipation (2·01, 1·62-2·49) was higher in those who went on to develop Parkinson's disease (n=1680) than in controls (n=8305).
A range of prediagnostic features can be detected several years before diagnosis of Parkinson's disease in primary care. These data can be incorporated into ongoing efforts to identify individuals at the earliest stages of the disease for inclusion in future trials and to help understand progression in the earliest phase of Parkinson's disease.
GBA-associated Parkinson's disease: Reduced survival and more rapid progression in a prospective longitudinal study.
Further insight into GBA related Parkinson's...
Mov Disord. 2014 Dec 1. doi: 10.1002/mds.26071. [Epub ahead of print]
Brockmann K, Srulijes K, Pflederer S, Hauser AK, Schulte C, Maetzler W, Gasser T, Berg D.
Parkinson's disease (PD) patients with GBA mutations show an earlier age at onset and more severe non-motor symptoms compared with PD patients without GBA mutations.
This study was undertaken to evaluate progression of motor and non-motor symptoms in sporadic PD patients depending on the mutational GBA status.
We used regression analysis to evaluate independent effects of the mutational GBA status, age at onset, age at examination, and disease duration on motor (Unified Parkinson's Disease Rating Scale [UPDRS]-III, Hoehn and Yahr [H&Y] stage, Levodopa [l-dopa]-equivalent-dosage) and non-motor characteristics (cognition and mood). Disease progression was assessed prospectively over 3 years.
The GBA-associated PD patients compared with non-mutation PD patients, although younger and with an earlier age at onset, show (1) a more rapid disease progression of motor impairment and cognitive decline and (2) reduced survival rates.
The mutational GBA status, rather than older age and age at onset, presents an important predictor for disease progression in this specific subgroup of PD patients.
Tuesday, 2 December 2014
Neurochem Res. 2014 Nov 30. [Epub ahead of print]
Dos Santos AB, Kohlmeier KA, Barreto GE.
Parkinson's disease (PD) is a neurobehavioral disorder characterized by motor symptoms and signs, and non-motor abnormalities such as olfactory dysfunction, pain, sleep disorders and cognitive impairment. Amongst these alterations, sleep disturbances play an important role in the pathology, but presence of disturbed sleep is not currently considered in diagnosis. However, sleeping problems may precede by many years the classic motor abnormalities of PD and should be clinically evaluated as a potential marker before disease onset. The first disturbance reported with this potential was the disorder REM sleep behaviour and currently several other disturbances have gained importance as potential markers, such as excessive daytime sleepiness, restless legs syndrome and new evidence also points to changes in circadian rhythms. Here we present a brief review of the major evidence indicating that sleep disturbances precede the motor symptoms in PD and neurodegeneration occurs in regions that could underlie these phenomena in order to provide support for the conclusion that disturbances of sleep should be considered as valuable preclinical markers for PD.
This is a study of potentially vital importance to our understand of the prodrome(s) of PD. Here the authors show that people with mild park...
What motivates Parkinson's disease patients to enter clinical trials? Valadas A, Coelho M, Mestre T et al. Parkinsonism Relat Disord....
Motor and non-motor correlates of olfactory dysfunction in Parkinson's disease. Berendse HW , Roos DS , Raijmakers P , Doty RL . J...