Neuropsychiatric characteristics of GBA-associated Parkinson disease

These findings support earlier observations about GBA-related PD... there does seem to be a tendency for increased neuro-psychiatric features, cognitive impairment and perhaps a more severe motor phenotype...

J Neurol Sci. 2016 Nov 15;370:63-69. doi: 10.1016/j.jns.2016.08.059. Epub 2016 Aug 30.

Swan M, Doan N, Ortega RA, Barrett M, Nichols W, Ozelius L, Soto-Valencia J, Boschung S, Deik A, Sarva H, Cabassa J, Johannes B, Raymond D, Marder K, Giladi N, Miravite J, Severt W, Sachdev R, Shanker V, Bressman S, Saunders-Pullman R.

http://www.jns-journal.com/article/S0022-510X(16)30550-0/abstract

Mutations in GBA1 are a well-established risk factor for Parkinson disease (PD). GBA-associated PD (GBA-PD) may have a higher burden of nonmotor symptoms than idiopathic PD (IPD). We sought to characterize the relationship between GBA-PD and neuropsychiatric symptoms. Subjects were screened for common GBA1 mutations. GBA-PD (n=31) and non-carrier (IPD; n=55) scores were compared on the Unified Parkinson Disease Rating Scale (UPDRS), Montreal Cognitive Assessment (MoCA), Beck Depression Inventory (BDI), and the State-Trait Anxiety Index (STAI). In univariate comparisons, GBA-PD had a greater prevalence of depression (33.3%) versus IPD (13.2%) (p<0.05). In regression models controlling for age, sex, disease duration, motor disability, and MoCA score, GBA-PD had an increased odds of depression (OR 3.66, 95% CI 1.13-11.8) (p=0.03). Post-hoc analysis stratified by sex showed that, among men, GBA-PD had a higher burden of trait anxiety and depression than IPD; this finding was sustained in multivariate models. Among women, GBA-PD did not confer greater psychiatric morbidity than IPD. These results suggest that GBA1 mutations confer greater risk of neuropsychiatric morbidity in PD, and that sex may affect this association.

Associations between plasma ceramides and cognitive and neuropsychiatric manifestations in Parkinson's disease dementia

Here we see differences in levels of ceramides not only in those PD patients with cognitive impairment, but also in those without cognitive impairment compared with controls... I think we are going to hear a lot more about ceramides in the future...

J Neurol Sci. 2016 Nov 15;370:82-87. doi: 10.1016/j.jns.2016.09.028. Epub 2016 Sep 19.

Xing Y, Tang Y, Zhao L, Wang Q, Qin W, Ji X, Zhang J, Jia J.

http://www.jns-journal.com/article/S0022-510X(16)30593-7/abstract

BACKGROUND:

The abnormal metabolism of ceramides may account for the pathogenesis of Parkinson's disease dementia (PDD). However, the effect of ceramides on cognitive domain impairments and neuropsychiatric symptoms of PDD remains unknown.

METHODS:

A total of 38 PDD, 40 PD with no cognitive impairment (PD-NC) and 40 normal controls were included. A series of cognitive tests and the Neuropsychiatric Inventory (NPI) were used to assess cognitive domains and neuropsychiatric symptoms. A non-fasting blood sample was obtained from each subject. Plasma ceramide levels were tested by HPLC-MS/MS analysis.

RESULTS:

C14:0 and C24:1 levels were significantly higher in PDD than in PD-NC and normal controls. Verbal memory was negatively correlated with C14:0 and C24:1. After controlling for confounding factors, C22:0, C20:0 and C18:0 were significantly associated with hallucinations, anxiety and sleep behavior disturbances, respectively.

CONCLUSION:

In PDD, the increase in ceramide levels was correlated with decreased memory function and associated with higher odds of multiple neuropsychiatric symptoms.

Brain MR Contribution to the Differential Diagnosis of Parkinsonian Syndromes: An Update

Up-to-date article about the use of MRI in parkinsonian syndromes... it is likely that MRI will play a leading role in the future identification of prodromal PD in my opinion...

Parkinsons Dis. 2016;2016:2983638. Epub 2016 Sep 28.

Rizzo G, Zanigni S, De Blasi R, Grasso D, Martino D, Savica R, Logroscino G.

https://www.hindawi.com/journals/pd/2016/2983638/

Brain magnetic resonance (MR) represents a useful and feasible tool for the differential diagnosis of Parkinson's disease. Conventional MR may reveal secondary forms of parkinsonism and may show peculiar brain alterations of atypical parkinsonian syndromes. Furthermore, advanced MR techniques, such as morphometric-volumetric analyses, diffusion-weighted imaging, diffusion tensor imaging, tractography, proton MR spectroscopy, and iron-content sensitive imaging, have been used to obtain quantitative parameters useful to increase the diagnostic accuracy. Currently, many MR studies have provided both qualitative and quantitative findings, reflecting the underlying neuropathological pattern of the different degenerative parkinsonian syndromes. Although the variability in the methods and results across the studies limits the conclusion about which technique is the best, specific radiologic phenotypes may be identified. Qualitative/quantitative MR changes in the substantia nigra do not discriminate between different parkinsonisms. In the absence of extranigral abnormalities, the diagnosis of PD is more probable, whereas basal ganglia changes (mainly in the putamen) suggest the diagnosis of an atypical parkinsonian syndrome. In this context, changes in pons, middle cerebellar peduncles, and cerebellum suggest the diagnosis of MSA, in midbrain and superior cerebellar peduncles the diagnosis of PSP, and in whole cerebral hemispheres (mainly in frontoparietal cortex with asymmetric distribution) the diagnosis of Corticobasal Syndrome.

Cognitive impairment in Parkinson's disease: Association between patient-reported and clinically measured outcomes

Interesting to see that these are the bits that patients notice when cognition starts to deteriorate... I always feel that patients have a bit of agnosia, at least for the motor features, and I wonder if its the same for cognition...

Parkinsonism Relat Disord. 2016 Sep 27. pii: S1353-8020(16)30383-2. doi: 10.1016/j.parkreldis.2016.09.025. [Epub ahead of print]

Mills KA, Mari Z, Pontone GM, Pantelyat A, Zhang A, Yoritomo N, Powers E, Brandt J, Dawson TM, Rosenthal LS.

http://linkinghub.elsevier.com/retrieve/pii/S1353-8020(16)30383-2

BACKGROUND:

In Parkinson's disease, the association between objective and patient-reported measures of cognitive dysfunction is unknown and highly relevant to research and clinical care.

OBJECTIVE:

To determine which cognitive domain-specific Montreal Cognitive Assessment (MoCA) subscores are most strongly associated with patient-reported cognitive impairment on question 1 (Q1) of the Movement Disorders Society Unified Parkinson's Disease Rating Scale (MDS-UPDRS).

METHODS:

We analyzed data from 759 PD participants and 481 persons without PD with in a retrospective, cross sectional analysis using data from the NINDS Parkinson's Disease Biomarkers Program (PDBP), a longitudinal, multicenter biomarker study. The relationship between a patient-reported cognitive rating (MDS-UPDRS q1.1) and objective cognitive assessments (MoCA) was assessed using multinomial logistic regression modeling and the outcomes reported as conditional odds ratios (cOR's) representing the relative odds of a participant reporting cognitive impairment that is "slight" versus "normal" on MDS-UPDRSq1.1 for a one unit increase in a MoCA sub-score, adjusted for age and education.

RESULTS:

In PD participants, changes in visuospatial-executive performance and memory had the most significant impact on subjective cognitive impairment. A 1-point increase in visuospatial-executive function decreased the chance of reporting a MDS-UPDRS Q1 score of "slight" versus "normal" by a factor of 0.686 (p < 0.001) and each 1 point improvement in delayed recall decreased the odds of reporting "slight" cognitive impairment by a factor of 0.836 (p < 0.001).

CONCLUSIONS:

Conversion from a PD patient's report of "normal" to "slight" cognitive impairment may be associated with changes in visuospatial-executive dysfunction and memory more than other cognitive domains.

Transcranial Sonography and DaTSCAN in Early Stage Parkinson's Disease and Essential Tremor

Both imaging modalities demonstrating reasonable diagnostic accuracy here. The problem with TCS is the subjectivity of the assessment and the fact that is (probably) a static risk marker rather than and diagnostic aid...

Eur Neurol. 2016 Oct 18;76(5-6):252-255. [Epub ahead of print]

Jesus-Ribeiro J, Freire A, Sargento-Freitas J, Sousa M, Silva F, Moreira F, Cunha MJ, Walter U, Januário C.

http://www.karger.com/Article/Abstract/452216

BACKGROUND:

The diagnosis of Parkinson's disease (PD) can sometimes be a challenge in the early stages of the disease. Both transcranial sonography (TCS) and DaTSCAN are recommended as auxiliary examinations for the differential diagnosis of PD; however, only few data exist regarding their diagnostic accuracy in the early stage of PD and essential tremor (ET).

METHODS:

We evaluated patients with clinically suspected diagnosis of PD at early stages (Hoehn and Yahr ≤2) or ET. All patients underwent DaTSCAN and TCS with a maximum interval of 6 months. Final diagnosis was established after 1-year follow-up.

RESULTS:

From the 63 patients recruited, 3 were excluded due to transcranial insonability and 2 for uncertain clinical diagnosis. The final clinical diagnosis was ET in 44.8% and PD in 55.2%. Compared to clinical diagnosis of PD, TCS had a sensitivity of 87.5% and specificity of 96.2%; DaTSCAN sensitivity was 84.4% and specificity was 96.2%. Both diagnostic tests demonstrated a substantial level of agreement (Cohen's kappa coefficient: 0.83, 95% CI 0.68-0.97, p < 0.001).

CONCLUSION:

TCS and DaTSCAN have similar diagnostic accuracy for the diagnosis of early stage PD versus ET.

Digitized Spiral Drawing: A Possible Biomarker for Early Parkinson's Disease

This is useful... it is likely that subtle motor dysfunction emerges a long time before a clinical diagnosis can be made on classical clinical criteria... evidence is accumulating on this subject. We need to find good ways of measuring this motor dysfunction and monitoring it in the pre-diagnostic phase...

PLoS One. 2016 Oct 12;11(10):e0162799. doi: 10.1371/journal.pone.0162799. eCollection 2016.

San Luciano M, Wang C, Ortega RA, Yu Q, Boschung S, Soto-Valencia J, Bressman SB, Lipton RB, Pullman S, Saunders-Pullman R.

http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0162799

INTRODUCTION:

Pre-clinical markers of Parkinson's Disease (PD) are needed, and to be relevant in pre-clinical disease, they should be quantifiably abnormal in early disease as well. Handwriting is impaired early in PD and can be evaluated using computerized analysis of drawn spirals, capturing kinematic, dynamic, and spatial abnormalities and calculating indices that quantify motor performance and disability. Digitized spiral drawing correlates with motor scores and may be more sensitive in detecting early changes than subjective ratings. However, whether changes in spiral drawing are abnormal compared with controls and whether changes are detected in early PD are unknown.

METHODS:

138 PD subjects (50 with early PD) and 150 controls drew spirals on a digitizing tablet, generating x, y, z (pressure) data-coordinates and time. Derived indices corresponded to overall spiral execution (severity), shape and kinematic irregularity (second order smoothness, first order zero-crossing), tightness, mean speed and variability of spiral width. Linear mixed effect adjusted models comparing these indices and cross-validation were performed. Receiver operating characteristic analysis was applied to examine discriminative validity of combined indices.

RESULTS:

All indices were significantly different between PD cases and controls, except for zero-crossing. A model using all indices had high discriminative validity (sensitivity = 0.86, specificity = 0.81). Discriminative validity was maintained in patients with early PD.

CONCLUSION:

Spiral analysis accurately discriminates subjects with PD and early PD from controls supporting a role as a promising quantitative biomarker. Further assessment is needed to determine whether spiral changes are PD specific compared with other disorders and if present in pre-clinical PD.

Transcranial sonography in dopa-responsive dystonia

This is interesting... GCH-1 mutations which cause DRD are a risk factor for PD it seems. Hyperechogenicity of the nigra also appears to be a risk factor for PD and is present in up to 80-90% of patients. Here we see a significant proportion of DRD patients have hyperechogenicity (albeit small sample size)....

Eur J Neurol. 2016 Oct 12. doi: 10.1111/ene.13172. [Epub ahead of print]

Svetel M, Tomić A, Mijajlović M, Dobričić V, Novaković I, Pekmezović T, Brajković L, Kostić VS.

http://onlinelibrary.wiley.com/doi/10.1111/ene.13172/abstract;jsessionid=D8D2A09917525ED2A1D143B1595D42E8.f01t04

BACKGROUND AND PURPOSE:

Mutations in the GCH1 gene, encoding GTP cyclohydrolase 1, the enzyme critically important for dopamine production in nigrostriatal neurons, are the most common cause of dopa-responsive dystonia (DRD), characterized predominantly by limb dystonia, although parkinsonian features may also be present. It has been suggested that DRD is a neurochemical rather than neurodegenerative disorder.

METHODS:

Transcranial brain sonography, which might be a risk marker for nigral injury, was obtained from 141 subjects divided into four groups: (i) 11 patients with genetically confirmed DRD; (ii) 55 consecutive patients with Parkinson's disease (PD); (iii) 30 patients diagnosed as isolated adult-onset focal dystonia; and (iv) 45 healthy controls (HCs).

RESULTS:

Substantia nigra hyperechogenicity was present in 63.6% of patients with DRD, which was significantly different in comparison to patients with dystonia (20%) and HCs (6.7%), but not in comparison to the PD group (87.3%). Also, values of the maximal areas of substantia nigra hyperechogenicity in patients with DRD were higher in comparison to HCs, but significantly lower than among the PD group.

CONCLUSIONS:

We suggested that the observed transcranial brain sonography features in patients with DRD might primarily be risk markers for particular clinical features (parkinsonism, dystonia) occurring in the specific genetic context (i.e. GCH1 mutations), or might reflect compensated neurodegenerative processes triggered by the long-lasting dopamine deficiency due to the profound delay in levodopa treatment in our patients with DRD.

Study of LRRK2 variation in tauopathy: Progressive supranuclear palsy and corticobasal degeneration

This paper confirms that LRRK2 mutations can be found in pathologically confirmed cases of PSP and CBD... however they are much more common in PD and LRRK2 remains the most common dominantly inherited form of PD...

Mov Disord. 2016 Oct 6. doi: 10.1002/mds.26815. [Epub ahead of print]

Sanchez-Contreras M, Heckman MG, Tacik P, Diehl N, Brown PH, Soto-Ortolaza AI, Christopher EA, Walton RL, Ross OA, Golbe LI, Graff-Radford N, Wszolek ZK, Dickson DW, Rademakers R.

BACKGROUND:

Mutations in the leucine-rich repeat kinase 2 gene (LRRK2) are the most common genetic cause of Parkinson's disease (PD). Unexpectedly, tau pathology has been reported in a subset of LRRK2 mutation carriers.

METHODS:

To estimate the frequency of pathogenic LRRK2 mutations and to evaluate the association of common LRRK2 variants with risk of primary tauopathies, we studied 1039 progressive supranuclear palsy (PSP) and 145 corticobasal degeneration patients from the Mayo Clinic Florida brain bank and 1790 controls ascertained at Mayo Clinic. Sanger sequencing of LRRK2 exons 30, 31, 35, and 41 was performed in all patients, and genotyping of all 17 known exonic variants with minor allele frequency >0.5% was performed in patients and controls.

RESULTS:

LRRK2 mutational screening identified 2 known pathogenic mutations (p.G2019S and p.R1441C), each in 1 PSP patient, the novel p.A1413T mutation in a PSP patient and the rare p.R1707K mutation in a corticobasal degeneration patient. Both p.A1413T and p.R1707K mutations were predicted damaging by at least 2 of 3 prediction programs and affect evolutionary conserved sites of LRRK2. Association analysis using common LRRK2 variants only showed nominal association of the p.L153L variant with PSP.

CONCLUSIONS:

Our study confirms the presence of pathogenic and potentially pathogenic LRRK2 mutations in pathologically confirmed primary tauopathies, albeit with low frequency. In contrast to PD, common LRRK2 variants do not appear to play a major role in determining PSP and corticobasal degeneration risk.

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.