Pathological α-synuclein transmission initiated by binding lymphocyte-activation gene 3

Second important synuclein paper of the weekend... its very encouraging to see evidence accumulating and drug targets being found... it fells like a good time to be involved in PD research...

Science. 2016 Sep 30;353(6307). pii: aah3374.

Mao X, Ou MT, Karuppagounder SS, Kam TI, Yin X, Xiong Y, Ge P, Umanah GE, Brahmachari S, Shin JH, Kang HC, Zhang J, Xu J, Chen R, Park H, Andrabi SA, Kang SU, Gonçalves RA, Liang Y, Zhang S, Qi C, Lam S, Keiler JA, Tyson J, Kim D, Panicker N, Yun SP, Workman CJ, Vignali DA, Dawson VL, Ko HS, Dawson TM.

http://science.sciencemag.org/content/353/6307/aah3374.long

Emerging evidence indicates that the pathogenesis of Parkinson's disease (PD) may be due to cell-to-cell transmission of misfolded preformed fibrils (PFF) of α-synuclein (α-syn). The mechanism by which α-syn PFF spreads from neuron to neuron is not known. Here, we show that LAG3 (lymphocyte-activation gene 3) binds α-syn PFF with high affinity (dissociation constant = 77 nanomolar), whereas the α-syn monomer exhibited minimal binding. α-Syn-biotin PFF binding to LAG3 initiated α-syn PFF endocytosis, transmission, and toxicity. Lack of LAG3 substantially delayed α-syn PFF-induced loss of dopamine neurons, as well as biochemical and behavioral deficits in vivo. The identification of LAG3 as a receptor that binds α-syn PFF provides a target for developing therapeutics designed to slow the progression of PD and related α-synucleinopathies.

A de novo compound targeting α-synuclein improves deficits in models of Parkinson's disease

This type of research is really important... it shows that a drug can reduce the formation and accumulation of alpha-synuclein (the key protein that underlies PD) and also reduce evidence of damage caused by it. The authors then show its activity in mouse models that have excessive alpha-synuclein... It is important to learn what other effects these compounds have before considering them to be potentially trialled as treatment, but very encouraging to know that things affect the burden of synuclein!!

Brain. 2016 Sep 27. pii: aww238. [Epub ahead of print]

Wrasidlo W, Tsigelny IF, Price DL, Dutta G, Rockenstein E, Schwarz TC, Ledolter K, Bonhaus D, Paulino A, Eleuteri S, Skjevik ÅA, Kouznetsova VL, Spencer B, Desplats P, Gonzalez-Ruelas T, Trejo-Morales M, Overk CR, Winter S, Zhu C, Chesselet MF, Meier D, Moessler H, Konrat R, Masliah E.

http://brain.oxfordjournals.org/content/early/2016/09/26/brain.aww238.long

Abstract

Abnormal accumulation and propagation of the neuronal protein α-synuclein has been hypothesized to underlie the pathogenesis of Parkinson's disease, dementia with Lewy bodies and multiple system atrophy. Here we report a de novo-developed compound (NPT100-18A) that reduces α-synuclein toxicity through a novel mechanism that involves displacing α-synuclein from the membrane. This compound interacts with a domain in the C-terminus of α-synuclein. The E83R mutation reduces the compound interaction with the 80-90 amino acid region of α-synuclein and prevents the effects of NPT100-18A. In vitro studies showed that NPT100-18A reduced the formation of wild-type α-synuclein oligomers in membranes, reduced the neuronal accumulation of α-synuclein, and decreased markers of cell toxicity. In vivo studies were conducted in three different α-synuclein transgenic rodent models. Treatment with NPT100-18A ameliorated motor deficits in mThy1 wild-type α-synuclein transgenic mice in a dose-dependent manner at two independent institutions. Neuropathological examination showed that NPT100-18A decreased the accumulation of proteinase K-resistant α-synuclein aggregates in the CNS and was accompanied by the normalization of neuronal and inflammatory markers. These results were confirmed in a mutant line of α-synuclein transgenic mice that is prone to generate oligomers. In vivo imaging studies of α-synuclein-GFP transgenic mice using two-photon microscopy showed that NPT100-18A reduced the cortical synaptic accumulation of α-synuclein within 1 h post-administration. Taken together, these studies support the notion that altering the interaction of α-synuclein with the membrane might be a feasible therapeutic approach for developing new disease-modifying treatments of Parkinson's disease and other synucleinopathies.

A new computer vision-based approach to aid the diagnosis of Parkinson's disease

I am interested in PD handwriting... but the analysis is not straightforward and there are many varied features... I don't agree with the last statement. I think the handwriting change may be relatively early. Many patients have showed me evolving change in handwriting prior to diagnosis... sometimes many years before...

Comput Methods Programs Biomed. 2016 Nov;136:79-88. doi: 10.1016/j.cmpb.2016.08.005. Epub 2016 Aug 26.

Pereira CR, Pereira DR, Silva FA, Masieiro JP, Weber SA, Hook C, Papa JP.

http://www.cmpbjournal.com/article/S0169-2607(16)30189-4/abstract

BACKGROUND AND OBJECTIVE:

Even today, pointing out an exam that can diagnose a patient with Parkinson's disease (PD) accurately enough is not an easy task. Although a number of techniques have been used in search for a more precise method, detecting such illness and measuring its level of severity early enough to postpone its side effects are not straightforward. In this work, after reviewing a considerable number of works, we conclude that only a few techniques address the problem of PD recognition by means of micrography using computer vision techniques. Therefore, we consider the problem of aiding automatic PD diagnosis by means of spirals and meanders filled out in forms, which are then compared with the template for feature extraction.

METHODS:

In our work, both the template and the drawings are identified and separated automatically using image processing techniques, thus needing no user intervention. Since we have no registered images, the idea is to obtain a suitable representation of both template and drawings using the very same approach for all images in a fast and accurate approach.

RESULTS:

The results have shown that we can obtain very reasonable recognition rates (around ≈67%), with the most accurate class being the one represented by the patients, which outnumbered the control individuals in the proposed dataset.

CONCLUSIONS:

The proposed approach seemed to be suitable for aiding in automatic PD diagnosis by means of computer vision and machine learning techniques. Also, meander images play an important role, leading to higher accuracies than spiral images. We also observed that the main problem in detecting PD is the patients in the early stages, who can draw near-perfect objects, which are very similar to the ones made by control patients.

Lower serum uric acid is associated with mild cognitive impairment in early Parkinson's disease: a 4-year follow-up study

Multiple studies suggest that elevated serum urate is protective against PD and reductions may lead to a more severe clinical picture... now that alteration of serum urate is a target in a phase 3 clinical trial we will see for sure how it affects PD...

J Neural Transm (Vienna). 2016 Sep 28. [Epub ahead of print]

Pellecchia MT, Savastano R, Moccia M, Picillo M, Siano P, Erro R, Vallelunga A, Amboni M, Vitale C, Santangelo G, Barone P.

http://link.springer.com/article/10.1007%2Fs00702-016-1622-6

Abstract

Cognitive deficits are common in Parkinson's disease (PD) and many patients eventually develop dementia; however, its occurrence is unpredictable. Serum uric acid (UA) has been proposed as a biomarker of PD, both in the preclinical and clinical phase of the disease. The aim of this pilot study was to evaluate relationships between baseline serum UA levels and occurrence of mild cognitive impairment (MCI) at 4-year follow-up in a cohort of early PD patients. Early PD patients, not presenting concomitant diseases, cognitive impairment or treatment possibly interfering with UA levels, underwent neuropsychological testing at baseline and 4-year follow-up. UA levels were determined in serum at baseline. MCI was found in 23 out of 42 PD patients completing 4-year follow-up. Patients presenting MCI had significantly higher age at onset and lower Frontal Assessment Battery scores at baseline as compared with patients cognitively intact. Logistic regression analysis showed that both serum UA levels (OR = 0.54, p = 0.044) and age (OR = 1.16, p = 0.009) contribute to the occurrence of MCI at 4-year follow-up. Our pilot study suggests that lower levels of serum UA in the early disease stages are associated to the later occurrence of MCI. These results need to be confirmed by further studies on larger samples.

Increased suicide risk and clinical correlates of suicide among patients with Parkinson's disease

These authors report a doubling in the rate of suicide in PD patients compared to controls... this feels pretty high and I cannot think of many, if any, patients I know of that have committed suicide. My impression is that it is more common in the atypical parkinsonisms. The authors do acknowledge this and say that the previous literature is mixed... some studies suggest higher risk and some lower risk. There is likely to be wide variability region to region and social support network and professional support (specialist nurses, doctors and support groups) are likely to be strong determinants... the results of such studies may not be generalisable to all populations...

Parkinsonism Relat Disord. 2016 Sep 6. pii: S1353-8020(16)30331-5. doi: 10.1016/j.parkreldis.2016.09.006. [Epub ahead of print]

Lee T, Lee HB, Ahn MH, Kim J, Kim MS, Chung SJ, Hong JP.

http://www.prd-journal.com/article/S1353-8020(16)30331-5/abstract

INTRODUCTION:

Parkinson's disease (PD) is a debilitating, neurodegenerative condition frequently complicated by psychiatric symptoms. Patients with PD may be at higher risk for suicide than the general population, but previous estimates are limited and conflicting. The aim of this study is to estimate the suicide rate based on the clinical case registry and to identify risk factors for suicide among patients diagnosed with PD.

METHODS:

The target sample consisted of 4362 patients diagnosed with PD who were evaluated at a general hospital in Seoul, South Korea, from 1996 to 2012. The standardized mortality ratio for suicide among PD patients was estimated. In order to identify the clinical correlates of suicide, case-control study was conducted based on retrospective chart review. The 29 suicide cases (age: 62.3 ± 13.7 years; females: 34.5%) were matched with 116 non-suicide controls (age: 63.5 ± 9.2 years; females 56.9%) by the year of initial PD evaluation.

RESULTS:

The SMR for suicide in PD patients was 1.99 (95% CI 1.33-2.85). Mean duration from time of initial diagnosis to suicide among cases was 6.1 ± 3.5 years. Case-control analysis revealed that male, initial extremity of motor symptom onset, history of depressive disorder, delusion, any psychiatric disorder, and higher L-dopa dosage were significantly associated with suicide among PD patients. Other PD-related variables such as UPDRS motor score were not significantly associated with death by suicide.

CONCLUSION:

Suicide risk in PD patients is approximately 2 times higher than that in the general population. Psychiatric disorders, and also L-dopa medication need further attention with respect to suicide.

Unsupervised home monitoring of Parkinson's disease motor symptoms using body-worn accelerometers.

This is not so much the future, as the present... there are now lots of devices that are available for monitoring of PD symptoms. One of the biggest issues is that almost all have been insufficiently validated... there are lots of examples of pilot studies and very few with replication... PD lends itself better than most other diseases to home monitoring... and this area will only grow over the coming years...

Parkinsonism Relat Disord. 2016 Sep 9. pii: S1353-8020(16)30334-0. doi: 10.1016/j.parkreldis.2016.09.009. [Epub ahead of print]

Fisher JM, Hammerla NY, Ploetz T, Andras P, Rochester L, Walker RW.

http://www.prd-journal.com/article/S1353-8020(16)30334-0/abstract

INTRODUCTION:

Current PD assessment methods have inherent limitations. There is need for an objective method to assist clinical decisions and to facilitate evaluation of treatments. Accelerometers, and analysis using artificial neural networks (ANN), have shown potential as a method of motor symptom evaluation. This work describes the development of a novel PD disease state detection system informed by algorithms based on data collected in an unsupervised, home environment. We evaluated whether this approach can reproduce patient-completed symptom diaries and clinical assessment of disease state.

METHODS:

34 participants with PD wore bilateral wrist-worn accelerometers for 4 h in a research facility (phase 1) and for 7 days at home whilst completing symptom diaries (phase 2). An ANN to predict disease state was developed based on home-derived accelerometer data. Using a leave-one-out approach, ANN performance was evaluated against patient-completed symptom diaries and against clinician rating of disease state.

RESULTS:

In the clinical setting, specificity for dyskinesia detection was extremely high (0.99); high specificity was also demonstrated for home-derived data (0.93), but with low sensitivity (0.38). In both settings, sensitivity for on/off detection was sub-optimal. ANN-derived values of the proportions of time in each disease state showed strong, significant correlations with patient-completed symptom diaries.

CONCLUSION:

Accurate, real-time evaluation of symptoms in an unsupervised, home environment, with this sensor system, is not yet achievable. In terms of the amounts of time spent in each disease state, ANN-derived results were comparable to those of symptom diaries, suggesting this method may provide a valuable outcome measure for medication trials.

Bone mass and vitamin D levels in Parkinson's disease: is there any difference between genders?

This study further confirms observations we made in our meta-analysis of bone health in PD... as with individuals that don't have PD... women are at higher risk than men...

J Phys Ther Sci. 2016 Aug;28(8):2204-9. doi: 10.1589/jpts.28.2204. Epub 2016 Aug 31.

Ozturk EA, Gundogdu I, Tonuk B, Kocer BG, Tombak Y, Comoglu S, Cakci A.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5011562/

[Purpose] The aim of this study was to determine the bone mineral density, vitamin D level, and frequencies of osteopenia and osteoporosis in patients with Parkinson's disease and to compare male and female patients with the controls separately. 

[Subjects and Methods] One hundred fifteen Parkinson's disease patients (47 males, 68 females; age range: 55-85 years) and 117 age- and gender-matched controls (47 males, 70 females) were enrolled in the study. Bone mineral density measured by dual-energy X-ray absorptiometry and serum D vitamin levels of each participant were recorded. 

[Results] The mean lumbar spine, femur neck, and total femur bone mineral density levels, T-scores, and vitamin D levels were found to be significantly lower in Parkinson's disease patients in both genders. Furthermore, osteoporosis rates were found be significantly higher only in female Parkinson's disease patients compared with female controls. 

[Conclusion] Data from the present study revealed that while osteoporosis was significantly higher only in female Parkinson's disease patients, all Parkinson's disease patients had lower bone mineral density scores and vitamin D levels compared with the controls regardless of gender, suggesting that clinicians should pay attention to the osteoporosis risk in Parkinson's disease and that adequate preventive measures should be taken in order to limit the future risk due to osteoporotic fractures.

Survival and dementia in GBA-associated Parkinson Disease: The mutation matters

This is really interesting isn't? I know that patients with GBA related PD tend to have a more severe form of Parkinson's and that dementia is common. I had assumed that the dementia was an important reason for shorter survival. The only concern I have is whether it is appropriate to adjust for dementia in the analysis... the problem is that although dementia is associated with the exposure (GBA status) and the outcome (death), it may be on the causal pathway between GBA status and death (which means that it ought not to be considered a confounding factor). I would be interested to see survival presented on two levels (dementia and non-dementia) rather than adjusted analysis....

Ann Neurol. 2016 Sep 15. doi: 10.1002/ana.24777. [Epub ahead of print]

Cilia R, Tunesi S, Marotta G, Cereda E, Siri PsyD C, Tesei S, Zecchinelli A, Canesi M, Mariani CB, Meucci N, Sacilotto G, Zini M, Barichella M, Magnani C, Duga S, Asselta R, Soldà G, Seresini A, Seia M, Pezzoli G, Goldwurm S.

http://onlinelibrary.wiley.com/doi/10.1002/ana.24777/full

Abstract

Objective To investigate survival, dementia and genotype-phenotype correlations in patients with Parkinson's disease (PD) with and without mutations on the Glucocerebrosidase gene (GBA). Methods We included 2764 unrelated consecutive PD patients: 123 GBA-carriers (67 mild-p.N370S, 56 severe mainly p.L444P) and 2641 non-carriers. Brain perfusion and dopamine transporter imaging was analyzed, including Dementia with Lewy Bodies (DLB) as additional control group. Results Multivariable analysis adjusted by gender, age at onset and disease duration attributed to GBA-carriers a greater risk for dementia (HR=3.16, p<0.001) and death (HR=1.85, p=0.002) than non-carriers. When dementia was introduced in the model as time-dependent covariate, the mortality risk remained greater in carriers (HR=1.65, p=0.016), suggesting that other clinical features are likely to contribute to reduced survival. At last examination GBA-carriers had worse motor symptoms, particularly non-dopaminergic features. Carriers of severe mutations had greater risk for dementia compared to mild mutations (p<0.001), but similar mortality risk. Consistent with clinical data, GBA-carriers showed reduced posterior parietal and occipital cortical synaptic activity and nigrostriatal function than PD non-carriers. Neuroimaging features of carriers of mild mutations overlapped with PD non-carriers, while carriers of severe mutations were closer to DLB. Interpretation Survival is reduced in GBA-carriers compared to non-carriers; this seems to be partially independent from the increased risk for early dementia. The risk for dementia is strongly modulated by the type of mutation. In the clinical continuum between PD and DLB, patients with GBA mutations seem to localize midway, with carriers of severe mutations closer to DLB than to idiopathic PD. 

Weight Change Is a Characteristic Non-Motor Symptom in Drug-Naïve Parkinson's Disease Patients with Non-Tremor Dominant Subtype: A Nation-Wide Observational Study

Weight loss has been reported in a variety of studies after a diagnosis of PD has been made... it is interesting to see that here it appears to associated with just the non-tremor dominant (presumably akinetic rigid) type of PD rather than the tremor dominant type... It may be another feature contributing to the real heterogeneity that we see in PD...

PLoS One. 2016 Sep 13;11(9):e0162254. doi: 10.1371/journal.pone.0162254. eCollection 2016.

Mun JK, Youn J, Cho JW, Oh ES, Kim JS, Park S, Jang W, Park JS, Koh SB, Lee JH, Park HK, Kim HJ, Jeon BS, Shin HW, Choi SA, Kim SJ, Choi SM, Park JY, Kim JY, Chung SJ, Lee CS, Ahn TB, Kim WC, Kim HS, Cheon SM, Kim JW, Kim HT, Lee JY, Kim JS, Kim EJ, Kim JM, Lee KS, Kim JS, Kim MJ, Baik JS, Park KJ, Kim HJ, Park MY, Kang JH, Song SK, Kim YD, Yun JY, Lee HW, Song IU, Sohn YH, Lee PH, Park JH, Oh HG, Park KW, Kwon DY.

http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0162254

Abstract

Despite the clinical impact of non-motor symptoms (NMS) in Parkinson's disease (PD), the characteristic NMS in relation to the motor subtypes of PD is not well elucidated. In this study, we enrolled drug-naïve PD patients and compared NMS between PD subtypes. We enrolled 136 drug-naïve, early PD patients and 50 normal controls. All the enrolled PD patients were divided into tremor dominant (TD) and non-tremor dominant (NTD) subtypes. The Non-Motor Symptom Scale and scales for each NMS were completed. We compared NMS and the relationship of NMS with quality of life between normal controls and PD patients, and between the PD subtypes. Comparing with normal controls, PD patients complained of more NMS, especially mood/cognitive symptoms, gastrointestinal symptoms, unexplained pain, weight change, and change in taste or smell. Between the PD subtypes, the NTD subtype showed higher total NMS scale score and sub-score about weight change. Weight change was the characteristic NMS related to NTD subtype even after controlled other variables with logistic regression analysis. Even from the early stage, PD patients suffer from various NMS regardless of dopaminergic medication. Among the various NMS, weight change is the characteristic NMS associated with NTD subtype in PD patients.

The clinical spectrum and natural history of pure akinesia with gait freezing

PAGF is a syndrome that can be recognised in the clinic and is considered a variant of PSP that tends to progress slowly... however PD and other pathologies have also been recognised at post mortem. As the authors say, defining the phenotype is important because it is often slowly progressive, associated with falls and lacks levodopa response...

J Neurol. 2016 Sep 13. [Epub ahead of print]

Owens E, Josephs KA, Savica R, Hassan A, Klassen B, Bower J, Maraganore D, Matsumoto J, Ahlskog JE.

http://link.springer.com/article/10.1007%2Fs00415-016-8278-x

Gait freezing as a presenting and relatively restricted condition is uncommon but a distinctive disorder. This entity was initially defined as "pure akinesia with gait freezing", and later a neuropathological substrate of progressive supranuclear palsy has been recognized. Limited studies have reported the clinical evolution after presentation, which is important for patient counseling. The objective of this study was to assess the demographic and clinical features, treatment-response, neuroimaging, and evolution of pure akinesia with gait freezing. A retrospective review of patients with this phenotype as previously defined was performed. Patients included had no or minimal limb rigidity and/or bradykinesia and no resting tremor, and all underwent neuroimaging of the brain after onset. Inclusion criteria were met by 30 patients, who were followed up to 21 years after symptom onset. During their course, 28 patients had falls (93 %), 12 patients had dysarthria (40 %), and 13 had handwriting changes (43 %). All patients had progression of their gait disorder over time, but with a variable interval until falls occurred. None of the patients developed vertical gaze palsy or met diagnostic criteria for an alternative parkinsonian disorder. Pure akinesia with gait freezing is a distinctive disorder that can be recognized in the clinic. Despite the previously reported progressive supranuclear palsy-like neuropathology, the clinical course is much less aggressive and disabling than classic Richardson syndrome, although fall risk eventually develops in nearly all patients. Bradykinesia, tremor, and rigidity do not develop, distinguishing pure akinesia with gait freezing from Parkinson's disease and other parkinsonian disorders.

Caffeine consumption and the 4-year progression of de novo Parkinson's disease

This is really interesting and there has been plenty about the relationship between caffeine and PD in the past... here the authors suggest that coffee drinkers have slower progression of a range of PD symptoms... whether this represents an effect on the underlying disease or improved symptom control remains to be seen...

Parkinsonism Relat Disord. 2016 Aug 4. pii: S1353-8020(16)30289-9. doi: 10.1016/j.parkreldis.2016.08.005. [Epub ahead of print]

Moccia M, Erro R, Picillo M, Vitale C, Longo K, Amboni M, Pellecchia MT, Barone P.

http://www.prd-journal.com/article/S1353-8020(16)30289-9/abstract

INTRODUCTION:

Higher caffeine consumption has been associated with reduced risk of Parkinson's disease (PD), and with a more benign progression of motor and non-motor symptoms (NMS). The present observational cohort study investigated motor and non-motor correlates of caffeine consumption in de novo PD.

METHODS:

79 newly diagnosed, drug naïve PD patients have been included and followed up for 4 years. The total caffeine use was calculated with the Caffeine Consumption Questionnaire. Following study variables were recorded at baseline, and after 2 and 4 years: UPDRS part III, UPDRS part IV, l-dopa Equivalent Daily Dose (LEDD), NMS Questionnaire (NMSQuest), and the time occurring from PD diagnosis to the need for l-dopa treatment. Age, gender and disease duration were included as covariates in the statistical models.

RESULTS:

The average daily caffeine consumption was 296.1 ± 157.2 mg. At Cox regression models, higher caffeine consumption was associated with a lower rate of starting l-Dopa treatment (HR = 0.630; 95%CI = 0.382-0.996). At the mixed-effects linear regression models considering the whole study period, each additional espresso cup per day (50 mg of caffeine) was more likely associated with 5-point lower UPDRS part III total score (Coef = -0.01; 95%CI = -0.02 to 0.00), with 50% reduced LEDD (Coef = -0.01; 95%CI = -0.15 to 0.00; p = 0.021), and with 5-point lower NMSQuest total score (Coef = -0.01; 95%CI = -0.01 to 0.00), but not with UPDRS part IV total score (Coef = -0.00; 95%CI = -0.00 to 0.00).

CONCLUSION:

Caffeine consumption was associated with a reduced accrual of motor and non-motor disability during 4-year follow-up in de novo PD, highlighting the rationale for using adenosine A2A antagonists since the early phases of PD.